Pharmaceutical compounds

ABSTRACT

A compound which is an arylimidazolyl isoxazole of formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof. The compound has activity in modulating the activity of p300 and/or CBP and is used to treat cancer, particularly prostate cancer.

FIELD OF THE INVENTION

The present invention relates to a series of novel arylimidazolylisoxazoles and to their use as modulators of p300 and/or CBP activity.

BACKGROUND TO THE INVENTION

Genetic and epigenetic modifications are critical to all stages ofcancer disease progression and epigenetic silencing has been shown to beimportant in the misregulation of genes involved in all of the hallmarksof cancer (Jones, P. A. and Baylin, S. B. (2007) “The epigenomics ofcancer”, Cell, Vol. 128, pp. 683-692). The underlying epigeneticmodifications that mediate regulation include DNA methylation and posttranslational histone modification. The latter includes methylation,acetylation, and ubiquitination. DNA-demethylating agents and histonedeacetylase inhibitors have shown anti-tumour activity and a number ofagents have been approved for use in the treatment of haematologicalmalignancies. The enzymes mediating histone modification, includinghistone acetyltransferases (HATs) which acetylate histone andnon-histone proteins, represent a wave of second generation targets forsmall molecule drug intervention.

Prostate cancer is one of the most common malignancies, and the secondleading cause of cancer mortality among men. The treatment forclinically localised disease is typically surgery or radiation therapy.For patients who recur systemically after definitive treatment, or whopresent with loco-regional or metastatic disease, long term diseasecontrol is the primary objective. Typically, this entails a series ofhormonal therapies that suppress androgen receptor (AR) signalling,since prostate cancers are exquisitely dependent upon AR function forsurvival and progression. Although AR targeted therapies inhibit tumourgrowth, disease is rarely eliminated and resistance to therapy isacquired through restored AR function. Progression to this ‘castrationresistant’ prostate cancer (CRPC) represents the lethal phenotype of theillness. It is estimated that between 50-60% of patients that developmetastatic disease have CRPC. Recently, several new therapeutic agentshave been approved for the treatment of CRPC. These however, providelimited clinical efficacy and serve only to prolong progression. Noveland tolerable agents are therefore necessary to make further gains inthe treatment of CRPC.

Multiple cellular mechanisms lead to the progression of CRPC. In allcases, acquisition of the CRPC phenotype is mediated via re-activationof the AR pathway. The acetyltransferase p300 directly regulates ARlevels and AR signalling activity in prostate cancer cells (Zhong etal., ‘p300 acetyltransferase regulates androgen-receptor degradation andPTEN-deficient prostate tumorigenesis,’ Cancer Res., Vol. 74, pp.1870-1880, 2014). Therapeutic modulation of p300 activity wouldtherefore target all known adaptive mechanisms which lead to thedevelopment of CRPC. Approved therapies and those in clinical studiesprimarily target only one or other of theses cellular mechanisms. Themodulation of p300 activity directly provides an opportunity to morebroadly modulate AR activity in CRPC than current and other experimentaltherapeutic strategies. In addition, resistance mechanisms to recentlyapproved agents have been shown to be AR-dependent (Cai, C. et al.,(2011) ‘Intratumoral de novo steroid synthesis activates androgenreceptor in castration-resistant prostate cancer and is up-regulated bytreatment with Cyp17A1 inhibitors,’ Cancer Res., Vol. 71, pp.6503-6513). Modulation of p300 should therefore inhibit resistance tocurrent therapies and potentially provide improved and sustainedefficacy and greater clinical utility.

In common with p300, the CREB (cyclic-AMP response element bindingprotein) binding protein (CBP) is an acetyltransferase that acts as atranscriptional co-activator in human cells. Both CBP and p300 possess asingle bromodomain (BRD) and a lysine acetyltransferase (KAT) domain,which are involved in the post-translational modification andrecruitment of histones and non-histone proteins. There is high sequencesimilarity between CBP and p300 in the conserved functional domains (seeDuncan A. Hay et al, JACS 2014, 135, 9308-9319). Modulation of CBPactivity therefore provides a promising route to the treatment ofcertain cancers. Accordingly, compounds that can modulate, e.g. inhibit,the activity of p300 and/or CBP are of interest in cancer therapy.

Tumours which harbour loss of function mutations in CBP become addictedto p300 and are uniquely sensitive to p300 inhibition (see Ogiwara etal. 2016 Cancer Discovery. 6; 430-445). Conversely tumours withmutations in p300 are uniquely sensitive to CBP inhibition. Geneticanalysis reveals that up to 15% of both non-small cell and small celllung tumours have these loss of function mutations. Similar mutationsare also found in up to 25% of bladder cancers. Accordingly, compoundsthat can modulate, eg inhibit, the activity of p300 and/or CBP are ofinterest in cancer therapy for tumours with these molecular changes.

Furthermore, CBP/p300 regulates the expression of key tumour immunecheckpoint proteins such as CTLA4/PD-L1 (see Casey et al., Science. 352;p 227-231, 2016) and plays an important role in the differentiation andfunction of T-regulatory cells which are involved in immune evasion bytumours. Accordingly, compounds that can modulate, eg inhibit, theactivity of p300 and/or CBP are of interest for cancer therapy incombination with agents that target the onco-immune system.

SUMMARY OF THE INVENTION

It has now been found that a series of novel compounds have activity inmodulating p300 and/or CBP activity. The compounds therefore havepotential utility in treating cancer, particularly prostate cancer.

Accordingly, the present invention provides a compound which is anarylimidazolyl isoxazole of formula (I):

wherein:

R⁰ and R, which are the same or different, are each H or C₁-C₆ alkylwhich is unsubstituted or substituted by OH, —OC(O)R′ or OR′ wherein R′is unsubstituted C₁-C₆ alkyl;

W is N or CH;

R¹ is a group which is unsubstituted or substituted and is selected fromC-linked 4- to 6-membered heterocyclyl; C₃-C₆ cycloalkyl; C₁-C₆ alkylwhich is unsubstituted or substituted by C₆-C₁₀ aryl, 5- to 12-memberedheteroaryl, C₃-C₆ cycloalkyl, OH, —OC(O)R′ or OR′ wherein R′ is asdefined above; and a spiro group of the following formula:

Y is —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—;

n is 0 or 1;

R² is a group selected from C₆-C₁₀ aryl, 5- to 12-membered heteroaryl,C₃-C₆ cycloalkyl and C₅-C₆ cycloalkenyl, wherein the group isunsubstituted or substituted and wherein C₆-C₁₀ aryl is optionally fusedto a 5- or 6-membered heterocyclic ring;

or a pharmaceutically acceptable salt thereof.

In another aspect the invention provides a pharmaceutical compositioncomprising an arylimidazolyl isoxazole of formula (I) as defined aboveor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. The pharmaceutical composition may further compriseone or more additional chemotherapeutic agents, for instance asmentioned below.

In a further aspect the invention provides an arylimidazolyl isoxazoleof formula (I) as defined above, or a pharmaceutically acceptable saltthereof, for use as a modulator of p300 and/or CBP activity.

DETAILED DESCRIPTION OF THE INVENTION

The term “substituted” includes the implicit provision that substitutionbe in accordance with the permitted valence of the substituted atom andthe substituent and that the substitution results in a stable compound(i.e. one that does not spontaneously undergo transformation such as arearrangement cyclisation, or elimination). In certain embodiments, asingle atom may be substituted with more than one substituent as long assuch substitution is in accordance with the permitted valence of theatom. In certain embodiments, a group that is substituted may besubstituted by one substituent group or it may be multiply substitutedon multiple carbon atoms. When any group defined herein is substituted,it is typically substituted by R¹⁰ as defined below. The group may, forinstance, be mono-, di- or tri-substituted by a group R¹⁰ as definedbelow.

In certain of the arylimidazolyl isoxazoles of formula (I), dependant onthe nature of the substituent, there may be chiral carbon atoms andtherefore the compounds may exist as stereoisomers. The inventionextends to all optical isomers such as stereoisomeric forms of thecompounds of formula (I), including enantiomers, diastereomers andmixtures thereof, such as racemates. The different stereoisomeric formsmay be separated or resolved one from the other by conventional methodsor any given isomer may be obtained by conventional stereoselective orstereospecific syntheses.

The compounds of the invention can exist in various tautomeric forms andit is to be understood that the invention encompasses all suchtautomeric forms.

It is understood that certain compounds of the invention contain bothacidic and basic groups and may therefore exist as zwitterions atcertain pH values.

It is also to be understood that any atom present in a compound of theinvention may be present in any available naturally-occurring isotopicform. For instance, a carbon atom may be ¹²C or ¹³C. A hydrogen atom maybe ¹H or ²H (deuterium).

As used herein, the terms “treat” and “treatment” refer to boththerapeutic treatment and prophylactic or preventative measures, whereinthe object is to prevent or slow down (lessen) an undesiredphysiological change or disorder, such as the development or spread ofcancer. “Treatment” can also mean prolonging survival as compared toexpected survival if not receiving treatment. Those in need of treatmentinclude those already with the condition or disorder as well as thoseprone to have the condition or disorder or those in which the conditionor disorder is to be prevented.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically withthe other ingredients comprising a formulation, and/or the patient beingtreated therewith.

A C₁₋₆ alkyl group or moiety is linear or branched. A C₁₋₆ alkyl groupis typically a C₁₋₄ alkyl group, or a C₁₋₂ alkyl group. Examples of C₁₋₆alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, n-pentyl, pentyl (i.e. 3-methylbut-1-yl),t-pentyl (i.e. 2-methylbut-2-yl), neopentyl (i.e.2,2-dimethylpropan-1-yl), n-hexyl, i-hexyl (i.e. 4-methylpentan-1-yl),t-hexyl (i.e. 3-methylpentan-3-yl) and neopentyl (i.e.3,3-dimethylbutan-1-yl). Typically a C₁₋₆ alkyl group is methyl (Me).For the avoidance of doubt, where two alkyl moieties are present in agroup, the alkyl moieties may be the same or different. A C₁₋₆ alkylgroup is unsubstituted or substituted, typically by one or more groupsR¹⁰ as defined below. For example, a C₁₋₆ alkyl group is unsubstitutedor substituted by 1, 2 or 3 groups R¹⁰ as defined below.

A C₁₋₆ alkylene group or moiety is an unsubstituted or substituted,linear or branched, saturated divalent aliphatic hydrocarbon group ormoiety containing 1 to 6 carbon atoms. Typically it is a C₁₋₃ alkylenegroup or moiety. Examples include methylene, ethylene, n-propylene andi-propylene groups and moieties. More typically it is methylene orethylene. When the alkylene group is substituted it is typicallysubstituted by a group R¹⁰ as defined below.

A C₃₋₆ cycloalkyl group or moiety is a saturated monovalent hydrocarbonring having 3 to 6 carbon atoms. It is thus a 3-, 4-, 5- or 6-memberedcarbocyclic ring containing only saturated bonds. Examples of acycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. In one embodiment a cycloalkyl group is cyclopropyl.

A 5- to 12-membered N-containing heteroaryl group or moiety is amonovalent 5- to 12-membered aromatic heterocyclic group which contains1, 2, 3, or 4 nitrogen atoms, typically 1 or 2 N atoms, and 0, 1 or 2other heteroatoms selected from O and S. It is linked via one of itsring N atoms or C atoms and is monocyclic or bicyclic. In one embodimentit is N-linked. In another embodiment it is C-linked. It may be, forexample, a 5- to 7-membered N-containing monocyclic heteroaryl group,for instance a 5- or 6-membered N-containing heteroaryl group such aspyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl,isothiazolyl, oxazolyl or isoxazolyl.

Examples of a 5- to 12-membered, N-containing heteroaryl group includepyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl andpyrrolopyrimidinyl groups. When substituted, a 5- to 12-membered,N-containing heteroaryl group is typically substituted by one or more,e.g. 1, 2 or 3, groups selected from unsubstituted C₁₋₄ alkyl and agroup R¹⁰ as defined below In one embodiment a 5- to 12-membered,N-containing heteroaryl group is unsubstituted.

A 4- to 6-membered C-linked heterocyclic group is a saturated monovalent4-, 5- or 6-membered heterocyclic ring containing at least oneheteroatom selected from O, N and S. It is linked via one of its ring Catoms. Examples include oxetane, thietane, azetidine, pyrrolidine,piperidine, tetrahydropyran, tetrahydrothiopyran and tetrahydrofuran. A4- to 6-membered C-linked, heterocyclic group is unsubstituted orsubstituted, typically by a group R¹⁰ as defined below. It may besubstituted on a ring carbon atom or on a ring N or S atom, as permittedby the valency of the atom.

A halogen or halo group is F, Cl, Br or I. Typically it is F, Cl or Br,more typically F.

A C₁₋₆ alkoxy group is linear or branched. It is typically a C₁₋₄ alkoxygroup, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy,n-butoxy, sec-butoxy or tert-butoxy group. A C₁₋₆ alkoxy group isunsubstituted or substituted, typically by one or more groups R¹⁰ asdefined below.

When in formula (I) R¹ is substituted, the substituents are typically 1,2 or 3 groups, more typically 1 or 2 groups, which are the same ordifferent and are selected from —SO₂Me, —SO₂-cyclopropyl, oxo (═O),C₁-C₆ alkoxy, OH, hydroxy(C₁-C₆)alkyl, halo, —NH₂, OH, CN, —OC(O)R″,—C(O)NHR″, —NHC(O)R″ and —COOR″, where R″ is H or C₁-C₆ alkyl optionallysubstituted by halo. In this context halo is typically F or

The 4- to 6-membered heterocyclyl is typically pyrrolidinyl,piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl. More typicallyit is pyrrolidin-3-yl, piperidin-4-yl, tetrahydropyran-4-yl ortetrahydrothiopyran-4-yl. Pyrrolidinyl and piperidinyl are typicallysubstituted on the ring N atom by —SO₂Me or C₁-C₆ alkyl (e.g. methyl).Tetrahydropyranyl is typically substituted on a ring C atom by C₁-C₆alkyl (e.g. methyl). Tetrahydrothiopyranyl is typically di-substitutedon the ring S atom by oxo.

The C₃-C₆ cycloalkyl group is typically cyclobutyl, cyclopropyl orcyclohexyl. Cycloalkyl is typically substituted by 1 or 2 groupsselected from halo, OH and C₁-C₆ alkoxy.

In the definition of R¹, C₁-C₆ alkyl substituted by 5- to 12-memberedN-containing heteroaryl is typically C₁-C₆ alkyl, for instance methyl orethyl, substituted by a 5- or 6-membered N-containing heteroaryl asdefined above. Typical examples of R¹ in formula (I) as defined aboveinclude the following groupings:

Each of R⁰ and R in formula (I) is independently H or C₁₋₆ alkyl whichis unsubstituted or substituted as defined above. Thus, for instance, R⁰is H and R is C₁₋₆ alkyl which is unsubstituted or substituted asdefined above; R is H and R⁰ is C₁₋₆ alkyl which is unsubstituted orsubstituted as defined above; each of R⁰ and R is H; or each of R⁰ and Ris C₁₋₆ alkyl which is unsubstituted or substituted as defined above. Ineach of these variants C₁₋₆ alkyl is typically methyl or ethyl,preferably methyl.

The integer n in formula (I) as defined above is 0 or 1, typically 0.

Y is typically —CH₂— or —CH₂CH₂— such that the ring containing it is a5- or 6-membered ring. When Y is —CH₂— the ring is pyrrolidin-2-one.When Y is —CH₂CH₂— the ring is piperidin-2-one. More typically Y is—CH₂CH₂— and the ring containing it is the 6-membered piperidin-2-onering.

R² is typically aromatic. It is therefore typically a C₆-C₁₀ aryl orC₅-C₆ heteroaryl group wherein C₆-C₁₀ aryl is optionally fused to a 5-or 6-membered heterocyclic ring. The C₆-C₁₀ aryl group is typicallyphenyl or naphthyl. A C₆-C₁₀ aryl group fused to a 5- or 6-memberedheterocyclic ring is typically a tetrahydrobenzofuranyl group.

When R² is a C₆-C₁₀ aryl group, for instance phenyl, it is typicallymono-, di- or tri-substituted. The substituents are 1, 2 or 3 groupswhich are the same or different and are typically selected from C₁-C₆alkyl, C₁-C₆ alkoxy, OH, cyano and halo, wherein the alkyl and alkoxygroups are each optionally substituted by halo. Halo in this context istypically F or Cl.

When the C₆-C₁₀ aryl group is phenyl, it is typically substituted by 1,2 or 3 groups, more typically 1 or 2 groups. The 1 or 2 groups aretypically positioned meta and/or para on the phenyl ring. The groups aretypically selected from halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy and CN.

R¹⁰ is selected from unsubstituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo,OH, C₁₋₆ alkoxy, —C(O)R′″, —C(O)₂R′″, —C(O)NR′″₂, oxo (═O), dioxo,—CH₂OR′″, —S(O)_(m)R′″, —NR′″C(O) R′″, —S(O)_(m)NR″″₂, and CF₃, whereinm is 1 or 2 and each R′″ is independently selected from H andunsubstituted C₁₋₆ alkyl. Typically R¹⁰ is selected from unsubstitutedC₁₋₆ alkyl, halo, OH, C₁₋₆ alkoxy, —C(O)R′″, —C(O)NR′″₂, oxo (═O) anddioxo.

In one preferred embodiment, the arylimidazolyl isoxazole of theinvention has the following formula (Ia):

wherein

R¹ is as defined above for formula (I);

Y′ is —CH₂— or —CH₂CH₂—; and

R^(2′) is a group selected from C₆-C₁₀ aryl optionally fused to a 5- or6-membered heterocyclic ring and C₅-C₆ heteroaryl, the group beingunsubstituted or mono-, di- or tri-substituted.

Compounds of the invention may contain asymmetric or chiral centres andthus exist in different stereoisomeric forms. The structural formulae(I) and (Ia) above encompass all stereoisomeric forms of the compoundsof the invention including diastereomers, enantiomers and racemicmixtures. Diastereomers and enantiomers may be obtained bystereoselective synthetic strategies, for instance via enantiomericsynthesis.

Stereoisomerism may occur in compounds of the present invention due tothe presence of an asymmetric carbon atom in the piperidin-2-one orpyrrolidin-2-one ring. Thus, as depicted in the structural formulabelow:

the carbon centre C^(x) is chiral and each of R, R⁰, W, R¹, Y, R² and nis as defined above for formula (I). The chirality at C^(x) means that acompound of the invention can be racemic or optically pure. Whenoptically pure it may be the R enantiomer or the S enantiomer, typicallythe S enantiomer.

Specific examples of compounds of the invention include those listed inthe following table:

No Structure Name 1

5-(5-(3,5-dimethylisoxazol-4-yl)-1- ((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1- phenylpyrrolidin-2-one 2

5-(5-(3,5-dimethylisoxazol-4-yl)-1- (tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1- phenylpyrrolidin-2-one 3

5-(5-(3,5-dimethylisoxazol-4-yl)-1- (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1- phenylpyrrolidin-2-one 4

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one 5

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one 6

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one 7

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 8

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 9

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 10

(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 11

(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 12

(S)-1-(3-chloro-5-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 13

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4- methoxyphenyl)pyrrolidin-2-one 14

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 15

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)pyrrolidin-2-one 16

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-propoxyphenyl)pyrrolidin-2-one 17

(S)-1-(4-chlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 18

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2-one 19

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2- one 20

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one 22

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2- one 23

(S)-1-(3,5-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 24

(S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 25

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-5- methoxyphenyl)pyrrolidin-2-one 26

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3- (trifluoromethoxy)phenyl)pyrrolidin- 2-one 27

(S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 28

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 29

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2- one 30

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2- one 31

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4- (trifluoromethyl)phenyl)pyrrolidin-2- one 32

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4- (trifluoromethoxy)phenyl)pyrrolidin- 2-one 33

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin- 2-one 34

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(o-tolyl)pyrrolidin-2-one 35

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin- 2-one 36

3-((S)-2-(5-(3,5-dimethylisoxazol-4- yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5- fluorobenzonitrile 37

(S)-1-(cyclohex-1-en-l-yl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 38

(S)-1-(4,5-difluoro-2-methylphenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 39

(S)-1-(3,4-dichloro-2-methylphenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 40

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one 41

(R)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 42

(R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 43

(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 44

(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 45

(R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 46

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 47

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidin-2-one 48

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one 49

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidin-2-one 50

(S)-1-(3-chloro-5-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 51

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 52

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 53

(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 54

(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2- yl)pyrrolidin-2-one 55

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one 56

(S)-1-(3,5-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 57

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2- one 58

(S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 59

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one E4

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 61

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 62

(S)-1-(4-chloro-3-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 63

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 64

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 65

(S)-1-(3-chloro-4-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 66

(S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 67

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one 68

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 69

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-dioxidotetrahydrothiophen-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 70

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 71

Tert-butyl (S)-3-(2-((S)-1-(3,4- difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1H-benzo[d]imidazol-1-yl)pyrrolidine-l-carboxylate 72

Tert-butyl (R)-3-(2-((S)-1-(3,4- difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1H-benzo[d]imidazol-1-yl)pyrrolidine-l-carboxylate 73

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 74

(S)-5-(1-((R)-1-(cyclopropylsulfonyl) pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl) pyrrolidin-2-one 75

(S)-5-(1-((R)-1-acetylpyrrolidin-3- yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 76

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 77

(5S)-1-(3,4-difluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 78

(5S)-1-(4-chloro-3-fluorophenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 79

(5S)-1-(3,4-dichlorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 81

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 80

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 82

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- beno[d]imidazol-2-yl)pyrrolidin-2- one83

(S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 84

(S)-1-(3-chloro-4-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 85

(S)-1-(4-chloro-3-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 86

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3- fluoro-4-methoxyphenyl)pyrrolidin- 2-one87

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 88

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 89

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1R,4s)-4- ethoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 90

(5S)-1-(3,4-dichlorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 91

(5S)-1-(4-chloro-3-fluorophenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 92

(5S)-1-(3-chloro-4-methoxyphenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 93

(5S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 94

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 95

(S)-1-(4-chloro-3-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 96

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 97

(S)-1-(2,3-dihydrobenzofuran-5-yl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 98

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 99

(S)-1-(3-chloro-4-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 100

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)- 1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin- 2-one 101

(S)-1-(4-chloro-3-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 102

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 103

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3- hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 104

(1R,3R)-3-(2-((S)-1-(3,4- difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1H-benzo[d]imidazol-1- yl)cyclopentylacetate 105

(1R,3R)-3-(2-((S)-1-(3-chloro-4- methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1H-benzo[d]imidazol-1- yl)cyclopentylacetate 106

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3- methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 107

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 108

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans- (1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 109

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one110

(S)-5-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 111

(S)-1-(3-chloro-4-methoxyphenyl)-5- (1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 112

(S)-1-(3-fluoro-4-methoxyphenyl)-5- (1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 113

(5S)-1-(3,4-difluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 114

(5S)-1-(3-chloro-4-methoxyphenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 115

(5S)-5-(5-(3,5-dimethylisoxazol-4- yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1- (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 116

5-(2-((S)-1-(3,4-difluorophenyl)-5- oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)piperidin-2- one 117

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 118

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1s,4R)-4- hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 119

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 120

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 121

(S)-1-(4-chloro-3-fluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4- methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 122

(S)-1-(3-chloro-4-methoxyphenyl)-5- (5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one123

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro- 4-methoxyphenyl)pyrrolidin-2-one 124

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 125

(1S,3r)-3-(2-((S)-1-(3,4- difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1H-benzo[d]imidazol-1-yl)cyclobutylacetate 126

(S)-5-(1-benzyl-5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 127

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one 128

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2- yl)pyrrolidin-2-one 129

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one 130

(S)-5-(1-((4,4- difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one 131

(S)-5-(1-benzyl-5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro- 4-methoxyphenyl)pyrrolidin-2-one 132

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3- ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 133

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3- (hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 134

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3- (hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 135

(S)-5-(1-(cyclopropylmethyl)-5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 136

(S)-3-(2-(1-(3,4-difluorophenyl)-5- oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)propyl acetate 137

(S)-5-(1-(3-aminocyclobutyl)-5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 138

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4- ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 139

(S)-5-(1-(3-aminocyclobutyl)-5-(3,5- dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 140

(S)-3-(2-(1-(3,4-difluorophenyl)-5- oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)-N-propylcyclobutanecarboxamide 141

(S)-5-(1-((R)-3,3- difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one 142

(S)-5-(1-((R)-3,3- difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 143

(S)-5-(1-((R)-3,3- difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one 144

(5S)-1-(3,4-difluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one(diastereoisomer 1) 145

(5S)-1-(3,4-difluorophenyl)-5-(5- (3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- one(diastereoisomer 2) 146

(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one 147

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one 148

(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one 149

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5- dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one 150

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one 151

(S)-1-(3-fluoro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one 152

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-di- fluorophenyl)piperidin-2-one 153

(S)-1-(4-chloro-3-fluorophenyl)-6-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one154

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one155

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3- fluoro-4-methoxyphenyl)piperidin-2- one156

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 157

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4- methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 158

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 159

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one 160

(S)-1-(4-chloro-3-fluorophenyl)-6-(5- (3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4- methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 161

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 162

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one163

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3- hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 164

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 165

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4- methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 166

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one 167

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5- dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin- 2-one 168

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2- yl)piperidin-2-one 169

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4- methoxyphenyl)piperidin-2-one 170

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro- 4-methoxyphenyl)piperidin-2-one 171

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)piperidin-2-one 172

(S)-1-(3-chloro-4-methoxyphenyl)-6- (1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one 173

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 174

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4- hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2- one 175

(S)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one176

(S)-1-(3,4-difluorophenyl)-5-(1- ((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 177

(S)-1-(3,4-difluorophenyl)-5-(1- ((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5-methylisoxazol- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one 178

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1- phenylpiperidin-2-one 179

(S)-1-(3-chloro-4-methoxyphenyl)-6- (1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2- one 180

(S)-6-(1-(3,3-difluorocyclobutyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)piperidin-2-one 181

(S)-6-(1-(3,3-difluorocyclobutyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro- 4-methoxyphenyl)piperidin-2-one 182

(1S,4r)-methyl 4-(2-((S)-1-(3,4- difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)cyclohexanecarboxylate 183

(1S,4r)-4-(2-((S)-1-(3,4- difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid 184

(1S,4)-4-(2-((S)-1-(3,4- difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)-N-propylcyclohexane carboxamide 185

(1S,4r)-4-(2-((S)-1-(3,4- difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H- benzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide 186

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6- fluoropyridin-3-yl)piperidin-2-one 187

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5- fluoropyridin-3-yl)piperidin-2-one 188

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3- yl)piperidin-2-one 189

(S)-1-(3-chloro-4-methoxyphenyl)-6- (6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H- imidazo[4,5-b]pyridin-2-yl)piperidin-2-one 190

(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4- hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one 191

(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H- imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2- one 192

(S)-1-(3-chloro-4-methoxyphenyl)-5- (3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H- imidazo[4,5-b]pyridin-2- yl)pyrrolidin-2-one193

(S)-5-(3-(4,4-difluorocyclohexyl)-6- (3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one 194

(S)-5-(3-(4,4-difluorocyclohexyl)-6- (3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3- fluoro-4-methoxyphenyl)pyrrolidin-2-one 195

(S)-6-(1-(4,4-difluorocyclohexyl)-5- (3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyrimidin- 5-yl)piperidin-2-one 196

(S)-1-(3,4-difluorophenyl)-6-(6-(3,5- dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2- yl)piperidin-2-one 197

(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin- 2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one 198

(S)-1-benzyl-5-(5-(3,5- dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2- oneand the pharmaceutically acceptable salts thereof.

A compound of the invention in which integer n=0 may be prepared by aprocess which comprises treating a compound of formula (II):

wherein each of R, R⁰, R¹, W and Y is as defined above for formula (I),with a boronic acid of formula R²—B(OH)₂ wherein R² is as defined abovefor formula (I), in the presence of Pd(PPh₃)₄ and Na₂CO₃ in aqueousethanol. The aqueous ethanol is typically 20-60% EtOH/water.

A compound of the invention in which integer n=0 may also be prepared bya process which comprises treating a compound of formula (III):

wherein each of R, R⁰, R¹, R², W and Y is as defined above for formula(I), with acetic acid at 60-100° C. or HCl/1,4-dioxane 20-90%.

A compound of the invention in which integer n is 1 may be prepared by aprocess which comprises treating a compound of formula (II) as definedabove with a compound of formula R²—CH₂Br in which R² is as definedabove for formula (I). Typically the reaction is conducted by addingsodium hexamethyldisilazane (NaHMDS) in THF to a solution of thecompound of formula (II) in DMF, and then adding a solution of thecompound of formula R²—CH₂Br in DMF.

The schemes shown below illustrate synthetic strategies, including theabove process steps, by which compounds of the invention may beproduced.

Route A: Non-Convergent Approach to γ-Lactam Analogues

Route B: Convergent Approach to γ-Lactam Analogues fromN-Arylpyroglutamic Acid

Route C: Reductive Amination Approach to γ-Lactam Analogues

Route D: Non-Convergent Approach to Valerolactam Analogues

Route E: Non-Convergent Approach to Azabenzimidazole Analogues

Route F: Convergent Approach to N-Alkyllactam Analogues

A key to the abbreviations used in all the above schemes is provided inthe Examples section below.

An arylimidazolyl isoxazole of formula (I) may be converted into apharmaceutically acceptable salt, and salts may be converted into thefree compound, by conventional methods. Pharmaceutically acceptablesalts include salts of inorganic acids such as hydrochloric acid,hydrobromic acid and sulfuric acid, and salts of organic acids such asacetic acid, oxalic acid, malic acid, methanesulfonic acid,trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. Inthe case of compounds bearing a free carboxy substituent, the saltsinclude both the above-mentioned acid addition salts and the salts ofsodium, potassium, calcium and ammonium. The latter are prepared bytreating the free benzarylimidazolyl isoxazole of formula (I), or anacid addition salt thereof, with the corresponding metal base orammonia.

An arylimidazolyl isoxazole of formula (I) or a pharmaceuticallyacceptable salt thereof is hereafter referred to as a compound of theinvention. Compounds of the invention have been found in biologicaltests to bind to the histone acetyltransferase (HAT), p300, and to CBP,as described in Example 199 below.

CREB binding protein (CBP) and its paralogue, p300, are twoclosely-related histone acetyl transferase co-factor proteins that areinvolved in a wide variety of cancer processes, including cellproliferation, apoptosis, cell cycle regulation and DNA damage response.CBP/p300 primarily functions as a transcription cofactor for a number ofoncoproteins including Jun, Fos and E2F. In addition, it acts as ahistone acetyltransferase and can also acetylate multiple non-histoneproteins such as p53, p73, and Rb. CBP/p300 has been reported to act asa tumour suppressor or as an oncoprotein dependent upon the nature ofthe cancer. Multiple studies have shown that p300 expression correlateswith disease progression and decreased survival.

CBP and p300 is up-regulated in human prostate cancer progression andhas been shown to be an AR co-activator (Debes, J. D., et al., (2003)‘p300 in prostate cancer proliferation and progression,’ Cancer Res.,Vol. 63, pp. 7638-7640; and Linja, M. J. et al., (2004) ‘Expression ofandrogen receptor coregulators in prostate cancer,’ Clin. Cancer Res.,Vol. 10, pp. 1032-1040).

p300 has recently been shown to directly regulate AR protein degradation(Zhong et al., 2014). p300 mediated AR acetylation was shown to inhibitAR ubiquitination and subsequent AR proteasome degradation (Zhong etal., 2014, cited above). The direct inhibition of p300 activity wouldtherefore promote AR degradation.

Given the high molecular heterogeneity of prostate cancer, theidentification of appropriate biomarkers is critical to the effectivepositioning and evaluation of targeted small molecule therapies. It isproposed that markers of the development of the CRPC phenotype via ARresurgence are used for patient stratification for the evaluation ofp300 modulators. These include PSA and circulating tumour cell (CTC)counts and the appearance of AR and AR splice variants in CTCs.

In terms of biomarkers to enable the monitoring of the modulation ofp300 activity, direct readouts include; determination of the AR and ARsplice variant levels;

modulation of AR activity by assessing levels of AR responsive genesincluding TMPRSS2 and KLK3. Other surrogate markers of AR functionalactivity include p21, c-Myc and p53. Given that multiple therapeuticagents which modulate AR activity are approved for use in CRPC,biomarkers to assess effects of p300 targeting and subsequent ARmodulation are already widely available and used in clinical settings.

Various types of cancer have been shown to express AR. In addition toprostate cancer, these include breast and bladder cancer. Modulation ofp300 activity would be expected to have therapeutic utility in thetreatment of such cancers and other indications in which AR isexpressed. In addition, it is feasible that p300 regulates the levels ofother nuclear hormone receptors, thereby further expanding the clinicalutility of p300 targeted agents.

A recent publication (Ogiwara et al. (2016) Cancer Discovery. 6;430-445) has shown that tumours which harbour loss of function mutationsin CBP are uniquely sensitive to p300 inhibition. Conversely tumourswith mutations of p300 are uniquely sensitive to CBP inhibition. In lungcancer, genetic analysis reveals that up to 15% of both non-small celland small cell tumours have these loss of function mutations. Similarmutations are also found in up to 25% of bladder cancers, as well as ina number of haematological malignancies, including lymphoma andleukaemia. Modulation of p300 and/or CBP would be expected to havetherapeutic utility in tumours which harbour these mutations

Further recent publications (Casey et al. (2016) Science. 352; 227-231;Ghosh et al. (2016) JBC on line) has shown that CBP/p300 regulates theexpression of key immune checkpoint proteins such as CTLA4/PDL1 as wellas the differentiation and function of t-regulatory cells. Modulation ofp300 and/or CBP would be expected to provide additional therapeuticutility when combined with agents that target the immune-oncologysystem.

A compound of the invention has activity as a modulator p300 and/or CBPactivity. It may therefore be used to treat cancer, or another clinicalcondition in which AR is expressed, or in cancers in which there isactivation of CBP and/or p300 function. The cancers that can be treatedinclude those which express AR or are otherwise associated with AR,those that harbour loss of function mutations in CBP or p300 and thosewhich have activated CBP and/or p300.

Cancers that may be treated include, but are not restricted to, prostatecancer, breast cancer, bladder cancer, lung cancer, lymphoma andleukaemia. The prostate cancer may be, for instance,castration-resistant prostate cancer (CRPC). The lung cancer may be, forinstance, non-small cell lung cancer or small cell lung cancer. A humanor animal patient suffering from cancer may thus be treated by a methodcomprising the administration thereto of a compound of the invention.The condition of the patient may thereby be improved or ameliorated.

A compound of the invention may thus be administered to a human oranimal patient in conjunction with radiotherapy or another therapeuticagent for the treatment of cancer. The present invention thereforefurther provides a combination therapy wherein a compound of theinvention, or a pharmaceutical composition comprising a compound of theinvention, is administered concurrently or sequentially withradiotherapy; or is administered concurrently sequentially or as acombined preparation with another therapeutic agent or agents, for thetreatment of cancer.

The or each other therapeutic agent will typically be an agentconventionally used for the type of cancer being treated. Classes oftherapeutic agents with which a compound of the invention is typicallycombined for the treatment of prostate cancer include androgen receptorantagonists, for instance Enzalutamide, and inhibitors of CYP17A1(17α-hydroxylase/C17,20 lyase), for instance Abiraterone; cytotoxicchemotherapy, for instance Docetaxel; for the treatment of lung cancerinclude cytotoxic chemotherapies, for instance cisplatin, carboplatin,docetaxel; for the treatment of bladder cancer include cytotoxicchemotherapies, for instance gemcitabine, cisplatin or immune therapies,for instance, bacillus calmette-guérin (BCG). Other classes of agentswith which a compound of the invention could be combined with includeimmune checkpoint inhibitors, for instance pembrolizumab, nivolumab,atezolizumab, ipilumumab; inhibitors of PARP (poly ADP ribosepolymerase) such as Olaparib; and inhibitors of CDK4/6 (cyclin-dependantkinase 4 and 6).

The term “combination” as used herein refers to simultaneous, separateor sequential administration. Where the administration is sequential orseparate, the delay in administering the second component should not besuch as to lose the beneficial effect of the combination.

The present invention further provides a product comprising

(a) a compound of the invention as defined above; and

(b) one or more other therapeutic agent or agents;

for separate, simultaneous or sequential administration in theprophylactic or therapeutic treatment of cancer, for instance thespecific types of cancer mentioned above. The other therapeutic agentmay be, for instance, an androgen receptor antagonist, an inhibitor ofCYP17A1, an inhibitor of PARP or an inhibitor of CDK4/6. Morespecifically, it may Enzalutamide, Abiraterone or Olaparib.

A compound of the invention can be administered in a variety of dosageforms, for example orally such as in the form of tablets, capsules,sugar- or film-coated tablets, liquid solutions or suspensions orparenterally, for example intramuscularly, intravenously orsubcutaneously. The compound may therefore be given by injection orinfusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Daily dosagescan vary within wide limits and will be adjusted to the individualrequirements in each particular case. Typically, however, the dosageadopted for each route of administration when a compound is administeredalone to adult humans is 0.0001 to 50 mg/kg, most commonly in the rangeof 0.001 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such adosage may be given, for example, from 1 to 5 times daily. Forintravenous injection a suitable daily dose is from 0.0001 to 1 mg/kgbody weight, preferably from 0.0001 to 0.1 mg/kg body weight. A dailydosage can be administered as a single dosage or according to a divideddose schedule.

A compound of the invention is formulated for use as a pharmaceutical orveterinary composition also comprising a pharmaceutically orveterinarily acceptable carrier or diluent. The compositions aretypically prepared following conventional methods and are administeredin a pharmaceutically or veterinarily suitable form. The compound may beadministered in any conventional form, for instance as follows:

A) Orally, for example, as tablets, coated tablets, dragees, troches,lozenges, aqueous or oily suspensions, liquid solutions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose,dextrose, saccharose, cellulose, corn starch, potato starch, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, maize starch, alginic acid, alginates or sodium starchglycolate; binding agents, for example starch, gelatin or acacia;lubricating agents, for example silica, magnesium or calcium stearate,stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners,wetting agents such as lecithin, polysorbates or lauryl sulphate. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. Such preparations may be manufactured in a knownmanner, for example by means of mixing, granulating, tableting, sugarcoating or film coating processes.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is present as such, ormixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia;dispersing or wetting agents may be naturally-occurring phosphatides,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides for example polyoxyethylene sorbitan monooleate.

The said aqueous suspensions may also contain one or more preservatives,for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by this addition of an antioxidant such as ascorbicacid. Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids an hexitol anhydrides,for example sorbitan monooleate, and condensation products of the saidpartial esters with ethylene oxide, for example polyoxyethylene sorbitanmonooleate. The emulsion may also contain sweetening and flavouringagents. Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, sorbitol or sucrose. In particular a syrup fordiabetic patients can contain as carriers only products, for examplesorbitol, which do not metabolise to glucose or which only metabolise avery small amount to glucose.

Such formulations may also contain a demulcent, a preservative andflavouring and coloring agents.

B) Parenterally, either subcutaneously, or intravenously, orintramuscularly, or intrasternally, or by infusion techniques, in theform of sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using thosesuitable dispersing of wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicpaternally-acceptable diluent or solvent, for example as a solution in1,3-butane diol.

Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition fattyacids such as oleic acid find use in the preparation of injectables.

C) By inhalation, in the form of aerosols or solutions for nebulizers.

D) Rectally, in the form of suppositories prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperature but liquid at the rectal temperature and will therefore meltin the rectum to release the drug. Such materials are cocoa butter andpoly-ethylene glycols.

E) Topically, in the form of creams, ointments, jellies, collyriums,solutions or suspensions.

The invention will be further described in the Examples and Reference

Examples which follow:

TABLE 1 Abbreviations AcOH glacial acetic acid aq aqueous Ac acetyl Boctert-butoxycarbonyl br broad CatCart ® catalytic cartridge CDI1,1-carbonyl-diimidazole d doublet DCM Dichloromethane DIPEAN,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide (ES⁺) electrospray ionization, positive mode Et Ethyl EtOAcethyl acetate FCS foetal calf serum HOBt 1-hydroxybenzotriazole hrhour(s) (M + H)⁺ protonated molecular ion Me methyl MeCN acetonitrileMeOH methanol MHz megahertz min minute(s) m/z: mass-to-charge ratio NMP1-methylpyrrolidin-2-one (N-methyl-2-pyrrolidone) NMR nuclear magneticresonance (spectroscopy) PdCl2dppf(1,1-Bis(diphenylphospino)ferrocene)palladium(II) dichloride Ph phenylPBS phosphate buffered saline PPh₃ triphenylphosphine q quartet RT roomtemperature RP HPLC reverse phase high performance liquid chromatographys singlet SCX solid supported cation exchange (resin) S_(N)Arnucleophilic aromatic substitution t triplet TBAF tetrabutylammoniumfluoride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuranTIPS-Cl chlorotriisopropylsilane TMB 3,3′,5,5′-tetramethylbenzidineXantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Procedures

All starting materials and solvents were either obtained from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated.

Column chromatography was performed on pre-packed silica (230-400 mesh,40-63 cartridges using the amount indicated. SCX was purchased fromSupelco and treated with 1M hydrochloric acid prior to use. Unlessstated otherwise the reaction mixture to be purified was first dilutedwith MeOH and made acidic with a few drops of AcOH. This solution wasloaded directly onto the SCX and washed with MeOH. The desired materialwas then eluted by washing with 1% NH₃ in MeOH.

Analytical Methods Reverse Phase High Performance Liquid Chromatography:

Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid; a Waters Xbridge BEH C18, 2.5 μm, 4.6×30 mmcolumn eluting with a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. UV spectra of the eluted peaks were measured using either adiode array or variable wavelength detector on an Agilent 1100 system.

Analytical LCMS was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid (Method 1); a Waters Xbridge BEH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of MeCN in aqueous 10 mMAmmonium Bicarbonate (Method 2). UV and mass spectra of the eluted peakswere measured using a variable wavelength detector on either an Agilent1200 with or an Agilent Infinity 1260 LCMS with 6120 single quadrupolemass spectrometer with positive and negative ion electrospray.

Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 μm,19×50 mm column using either a gradient of either 0.1% Formic Acid inMeCN in 0.1% aqueous Formic Acid or a gradient of MeCN in aqueous 10 mMAmmonium Bicarbonate; or a Waters Xbridge BEH C18, 5 μm, 19×50 mm columnusing a gradient MeCN in aqueous 10 mM Ammonium Bicarbonate. Fractionswere collected following detection by UV at a single wavelength measuredby a variable wavelength detector on a Gilson 215 preparative HPLC orVarian PrepStar preparative HPLC; by mass and UV at a single wavelengthmeasured by a ZQ single quadrupole mass spectrometer, with positive andnegative ion electrospray, and a dual wavelength detector on a WatersFractionLynx LCMS.

Chiral preparative HPLC was carried out using a Gilson Diacel ChiralpakIA or IB, 5 μm, 20×250 mm, 60 mn runs, 1.0 mL/mn, using the followingsolvent systems:

Method A—10% EtOH in 4:1 isohexane (0.1% DEA):DCM (Diacel Chiralpak IA)Method B—10% EtOH in 4:1 isohexane (0.1% DEA):DCM (Diacel Chiralpak IA)Method C—20% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IA)Method D—35% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IC)Method E—35% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IC)Method F—20% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IA)1H NMR Spectroscopy: 1H NMR spectra were acquired on a Bruker Avance IIIspectrometer at 400 MHz. Either the central peaks of chloroform-d,dimethylsulfoxide-d6 or an internal standard of tetramethylsilane wereused as references.

¹H NMR Spectroscopy:

¹H NMR spectra were acquired on a Bruker Avance III spectrometer at 400MHz using residual undeuterated solvent as reference

REFERENCE EXAMPLES General Route A: Non-Convergent Approach to γ-LactamAnalogues 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (IntermediateA)

PdCl₂(dppf) (60 g, 82 mmol) was added to a stirring mixture of potassiumcarbonate (407 g, 2947 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid(180 g, 1277 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (216 g, 982 mmol)in 4:1 Dioxane/water (3 L). The reaction mixture was stirred at 90° C.for 18 h. After cooling to RT the mixture was diluted with water (1 L)and extracted with ethyl acetate (1×2 L and 1×1 L). Combined organicswere eluted through a Celite pad and evaporated under reduced pressure.DCM (1 L) was added to the crude product and the resultant solution waspurified in three batches; each batch (400 mL) being loaded onto a 1 kgsilica plug and eluting with DCM. Fractions from all three plugs wereanalysed by HPLC; product fractions were combined and concentrated invacuo to afford 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (177.6g, 76%) as a light yellow solid; Rt 2.08 min (method 1), m/z 237 (M+H)+(ES+).μ

(R)—N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)pyrrolidin-3-amine(B1)

(R)-3-methyl-1-(methylsulfonyl)pyrrolidine hydrochloride (4.9 g, 24.54mmol) and TEA (11.40 ml, 82 mmol) were dissolved in DMF (30 ml, 387mmol), 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (3.86 g, 16.36mmol) added, and stirred at 45° C. for 30 h. The mixture was evaporatedin vacuo, and the residue dissolved in EtOAc (200 mL), washed with water(2×100 mL) and brine (50 mL), dried (MgSO₄), filtered and evaporated invacuo. The residual orange solid was purified by chromatography onsilica gel (220 g column, 0-100% EtOAc in (50% DCM/isohexane) to give(R)—N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)pyrrolidin-3-amine(5.3 g, 85%); Rt 1.99 min (method 2); m/z 381 (M+H)+ (ES+).

(R)-4-(3,5-dimethylisoxazol-4-yl)-N1-(1-(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine(Intermediate C1)

(R)—N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)pyrrolidin-3-amine(5.2 g, 13.67 mmol) was dissolved in THF/water (1:1, 400 mL) thenaqueous concentrated ammonia (10.65 mL, 273 mmol) and sodium dithionite(23.80 g, 137 mmol) were added and the reaction stirred at RT for 1 h.The layers were separated and the aqueous extracts were extracted withEtOAc (20 mL). The combined organics washed with brine (20 mL), dried(MgSO₄), filtered and evaporated in vacuo to give(R)-4-(3,5-dimethylisoxazol-4-yl)-N1-(1-(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine(3.89 g, 72%) as a pink foam; Rt 1.68 min (method 2); m/z 351 (M+H)+(ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine(B2)

Tetrahydro-2H-pyran-4-amine (2.63 ml, 25.4 mmol) was dissolved in dryTHF (10 ml, 122 mmol) and TEA (8.85 ml, 63.5 mmol) and cooled to 0° C.4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole Intermediate A (5 g,21.17 mmol) was added and the reaction stirred at 60° C. for 16 hours.Further amine/base (½ molar equivalent) added and heated at 60° C.overnight. The reaction mixture was poured onto water (100 mL), Thesolid formed was filtered under vacuum, washed with water (50 mL),isohexane (100 mL) and dried in vacuo to giveN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine(6.5 g, 96%) as a bright orange solid; Rt 2.13 min (method 2); m/z 318(M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

(C2)

Sodium dithionite (75 g, 431 mmol) was added to a solution ofN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine(13.1 g, 40.9 mmol) and concentrated ammonia (32 ml, 822 mmol) inTHF/water (1:1, 200 mL) and the reaction mixture stirred at RT for 2hours. The reaction mixture was partitioned between EtOAc (200 mL) andbrine (100 mL), the phases separated and the organics dried over MgSO₄,filtered and concentrated in vacuo to give a sticky pink foam. The foamwas slurried in diethyl ether (150 mL) overnight then collected byfiltration to yield4-(3,5-dimethylisoxazol-4-yl)-N¹-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine(8.57 g, 70%) as a pink solid; Rt 0.83 min (method 1); m/z 288 (M+H)+(ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine(B3)

To a mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (6.60g, 27.9 mmol) and 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (5 g, 33.5mmol) in DMF (40 mL) was added TEA (8.56 ml, 61.4 mmol). The mixture wasstirred at 60° C. for 18 h, then quenched in ice water (200 mL). Thesolid was collected by filtration and washed with water to afford4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (10.2 g, 92%) as a bright orange solid; Rt 1.91 min (method1); m/z 366 (M+H)+ (ES+).

4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (C3)

4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (10.2 g, 27.9 mmol) was added to a solution of sodiumdithionite (48.6 g, 279 mmol) and ammonium hydroxide (78 mL, 558 mmol)in THF (150 ml) and water (100 mL). The reaction mixture stirred at RTfor 18 h, then concentrated in vacuo to remove organics. The remainingaqueous layer (containing solid present) was filtered under vacuum,washed with water (2×100 mL) and pulled to dryness. The solid wastransferred to a flask and triturated with ether. Filtration and pullingto dryness afforded4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (4.94 g, 48%) as a light beige solid; Rt 1.24 min (method1); m/z 336 (M+H)+ (ES+).

(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexan-1-ol(B4)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (32.6 g, 138 mmol),trans-4-aminocyclo hexanol (18.5 g, 160.6 mmol), and potassium carbonate(40 g, 289 mmol) were heated to reflux in acetonitrile (500 mL) for 3 h.The mixture was diluted dropwise with water (2 L) whilst stirringvigorously. The resulting precipitate was collected by filtration toyield(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanol(56.5 g, 99%) as a bright orange solid; Rt 2.00 min (method 1); m/z 332(M+H)+ (ES+).

(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexan-1-ol(C4)

Sodium dithionite (300 g, 1465 mmol) was added slowly in three (ca. 100g) portions to a mixture of(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanol(56 g, 135 mmol), concentrated ammonia (110 mL, 2825 mmol), THF/water(1:1, 1 L then stirred at room temperature for a total of 40 minutes.The mixture was diluted with water (2 L) then the precipitate wascollected by filtration to yield a pink solid. The solid wasco-evaporated in acetonitrile (500 mL) to afford(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexan-1-ol(33 g, 80%) as a pink solid; Rt 1.05 min (method 1); m/z 302 (M+H)+(ES+).

(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydrothiophene1,1-dioxide (B5)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.92 g,12.35 mmol) and (S)-3-aminotetrahydrothiophene 1,1-dioxide (1.67 g,12.35 mmol) was stirred in dry THF (20 mL) and TEA (6.89 ml, 49.4 mmol)was added. The reaction was stirred at RT for 72 h, then poured into icewater (100 mL). A solid precipitated which was collected by filtration.The solid was washed with water to afford after filtration(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydrothiophene1,1-dioxide (B5) (4.47 g, 100%) as a bright orange solid; Rt 1.88 min(method 1); m/z 352 (M+H)+ (ES+).

(S)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydrothiophene1,1-dioxide (C5)

(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydrothiophene1,1-dioxide (3.42 g, 9.73 mmol) was dissolved in water (150 mL) and THF(150 mL). ammonium hydroxide solution (7.58 mL, 195 mmol) and sodiumdithionite (16.95 g, 97 mmol) were added and the reaction stirred at RTfor 2 h. EtOAc (200 mL) was added, the mixture transferred to aseparating funnel and washed sequentially with 1M NaOH (2×200 mL) andbrine (100 mL). The organic phase was dried (MgSO₄), filtered andconcentrated in vacuo to give an off white solid, which was trituratedwith ether and collected by filtration to afford(S)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydrothiophene1,1-dioxide (1.4 g, 42%) as a light pink fluffy solid; Rt 1.26 min(method 1); m/z 322 (M+H)+ (ES+).

tert-butyl(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(B6)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (6.34 g,26.8 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (5 g,26.8 mmol) was stirred in dry THF (100 mL) and TEA (11.23 mL, 81 mmol)was added. The reaction was stirred at 40° C. for 72 h then heated to50° C. and stirred for 18 h. After cooling to RT, the reaction mixturewas poured into ice water (300 mL). The mixture was extracted with ethylacetate (2×500 mL). The combined organics were dried (MgSO₄) andconcentrated in vacuo to afford (S)-tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(11.57 g, 99%) as a thick orange oil; Rt 1.26 min (method 1); m/z 322(M+H)+ (ES+).

tert-butyl(S)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate(C6)

(S)-Tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(10.8 g, 26.8 mmol) was dissolved in water (500 mL) and THF (500 mL).Concentrated ammonia (20.90 mL, 537 mmol) and sodium dithionite (46.7 g,268 mmol) were added and the reaction stirred at RT for 18 h. EtOAc (500mL) was added, the mixture transferred to a separating funnel and washedsequentially with 1M NaOH (400 mL) and brine (200 mL). The organic phasewas dried (MgSO4), filtered and concentrated in vacuo to give an offwhite solid. The material was triturated with ether and collected byfiltration. The filtrate was concentrated in vacuo to afford a lightfluffy off white solid. After LCMS and NMR analysis the trituratedmaterial and the material obtained from the filtrate were combined toafford (S)-tert-butyl3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate(7.64 g, 76%) as an off white fluffy solid; Rt 1.98 min (method 1); m/z273 (M-Boc+H)+ (ES+).

tert-butyl(R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(B6)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (10 g,42.3 mmol) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (7.89 g,42.3 mmol) was stirred in dry THF (100 mL) and TEA (17.70 mL, 127 mmol)was added. The reaction was stirred at RT for 18 h, then heated to 40°C. and stirred for 72 h, then heated to 50° C. and stirred for 18 h.After cooling to RT, the reaction mixture was poured into ice water (300mL). The mixture was extracted with ethyl acetate (2×500 mL). Thecombined organics were dried (MgSO₄) and concentrated in vacuo to afford(R)-tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(17.85 g, 96%) as a thick orange oil; Rt 2.55 min (method 1); m/z 403(M+H)+ (ES+).

tert-butyl(R)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate(C6)

(R)-Tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(17.04 g, 42.3 mmol) was dissolved in THF/water (1:1, 1 L). Ammonia(33.0 mL, 847 mmol) and sodium dithionite (73.7 g, 423 mmol) were addedand the reaction stirred at RT for 18 h. EtOAc (500 mL) was added, themixture transferred to a separating funnel and washed sequentially with1M NaOH (400 mL) and brine (200 mL). The organic phase was dried(MgSO₄), filtered and concentrated in vacuo to give a light peach fluffysolid. The material was triturated with ether and collected byfiltration. The filtrate was concentrated in vacuo to afford a lightfoam. The triturated material and the material obtained from thefiltrate were combined to afford (R)-tert-butyl3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate (13.58 g, 85%) as a light peach fluffy solid;Rt 1.98 min (method 1); m/z 273 (M-Boc+H)+ (ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-methylpyrrolidin-3-amine(B7)

1-Methylpyrrolidin-3-amine (1.060 g, 10.58 mmol) was added to asuspension of 1-methylpyrrolidin-3-amine, bis-hydrochloride (2.75 g,15.88 mmol) in DIPEA (8.32 mL, 47.6 mmol) and THF (30 mL, 366 mmol) andstirred and sonicated for 15 min. A solution of4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.5 g, 10.58 mmol) inDMF (5 mL, 64.6 mmol) was added to the suspension and the reactionstirred at 50° C. for 20 h then for a further 20 h at 70° C. More1-Methylpyrrolidin-3-amine (1.060 g, 10.58 mmol) was added and stirredfor 5 h. Further DMF (10 mL, 129 mmol) was added and stirred for afurther 20 h. The solvents were evaporated in vacuo and the residuepartitioned between EtOAc (100 mL) and saturated aqueous sodiumhydrogenocarbonate (100 mL) and the layers separated. The aqueous phasewas extracted with further EtOAc (2×50 mL) and the combined organicextracts washed with water (50 mL) and brine (50 mL). The solution wasdried (MgSO₄), filtered and evaporated in vacuo. The residual gum waspurified by chromatography on the Companion (180 g column, 0-100% EtOAcin DCM, followed by 0-50% (DCM/MeOH/NH₃ (80:20:1) in DCM, loaded in DCM)to giveN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-methylpyrrolidin-3-amineIntermediate B7 (2.5 g, 75%); Rt 1.10 min (method 1); m/z 317 (M+H)+(ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-methylpyrrolidin-3-yl)benzene-1,2-diamine(C7)

Intermediate B7 (2.5 g, 7.90 mmol) and concentrated ammonia (5 ml, 128mmol) were dissolved in THF/water (1:1, 150 mL). Sodium dithionite(13.76 g, 79 mmol) was added and the reaction mixture stirred at RT for3 h. The layers were separated, the aqueous extracted with EtOAc (100mL), the combined organics washed with brine (50 mL), dried (MgSO₄),filtered and evaporated in vacuo to give4-(3,5-dimethylisoxazol-4-yl)-N¹-(1-methylpyrrolidin-3-yl)benzene-1,2-diamineIntermediate C7 (1.8 g, 77%) as a buff coloured solid; Rt 0.31 min(method 1); m/z 287 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N-((1r,4r)-4-methoxycyclohexyl)-2-nitroaniline(B8)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (0.609 g, 2.58 mmol)was dissolved in dry THF (20 ml) and TEA (1.079 ml, 7.74 mmol).(1r,4r)-4-methoxycyclohexanamine (0.4 g, 3.10 mmol) was added and thereaction warmed to 60° C. and left to stir at rt for 84 h. After coolingto rt the reaction mixture was poured into ice water (100 ml), thenextracted with ethyl acetate (2×100 ml). Combined organics wereconcentrated in vacuo (azeotroping with acetonitrile) to afford thecrude4-(3,5-dimethylisoxazol-4-yl)-N-((1r,4r)-4-methoxycyclohexyl)-2-nitroaniline(1.1 g, 3.12 mmol, >100%), which was used without purification in thenext step; Rt 2.40 min (method 1); m/z 346 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-(1r,4r)-4-methoxycyclohexyl)benzene-1,2-diamine(C8)

4-(3,5-Dimethylisoxazol-4-yl)-N-((1r,4r)-4-methoxycyclohexyl)-2-nitroaniline(0.89 g, 2.58 mmol) was dissolved in water (50 mL) and THF (50 mL).Concentrated ammonia (2.0 mL, 51.5 mmol) and sodium dithionite (4.49 g,25.8 mmol) were added and the reaction stirred at RT for 2 h. EtOAc (250mL) was added, the mixture transferred to a sep funnel and washedsequentially with 1M NaOH (150 mL) and brine (100 mL). The organic phasewas passed through a phase sep cartridge and concentrated in vacuo toafford4-(3,5-dimethylisoxazol-4-yl)-N¹-((1r,4r)-4-methoxycyclohexyl)benzene-1,2-diamine(680 mg, 81%) as an orange solid; Rt 1.24 min (method 1); m/z 316 (M+H)+(ES+).

3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (B9)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2 g, 8.47 mmol) wasdissolved in dry THF (50 mL) and TEA (4.72 mL, 33.9 mmol).3-Aminotetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (1.89 g, 10.16mmol) was added and the reaction warmed to 60° C. and left to stir at rtfor 84 h. DMF (20 mL) was added and the reaction mixture heated at 70°C. for 18 h. After cooling to rt the reaction mixture was poured intoice water (200 mL), then extracted with ethyl acetate (2×200 mL).Combined organics were concentrated in vacuo (azeotroping withacetonitrile) to afford3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (3.6 g, 8.37 mmol, 99%) as an orange solid; Rt 1.93 min(method 1); m/z 366 (M+H)+ (ES+).

3-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (C9)

3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (3.09 g, 8.46 mmol) was dissolved in THF/water (1:1, 400ml). Concentrated ammonia (6.59 ml, 169 mmol) and sodium dithionite(14.72 g, 85 mmol) were added and the reaction stirred at RT for 2 h.EtOAc (500 mL) was added, the mixture transferred to a sep funnel andwashed sequentially with 1M NaOH (400 mL) and brine (200 mL). Theorganic phase was passed through a PhaseSep© cartridge and concentratedin vacuo to afford3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran1,1-dioxide (1.80 g, 62%) as an off white foam; Rt 1.31 min (method 1);m/z 336 (M+H)+ (ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)piperidin-4-amine(B10)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2 g, 8.47 mmol) wasdissolved in dry THF (50 ml) and TEA (4.72 ml, 33.9 mmol).1-(methylsulfonyl)piperidin-4-amine hydrochloride (2.182 g, 10.16 mmol)was added and the reaction warmed to 60° C. and left to stir at rt for84 h. DMF (20 ml) was added and the reaction mixture heated at 70° C.for 18 h. After cooling to rt the reaction mixture was poured into icewater (200 ml), then extracted with ethyl acetate (2×200 ml). Combinedorganics were concentrated in vacuo (azeotroping with acetonitrile) toaffordN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)piperidin-4-amine(4.67 g, 11.72 mmol, 138% yield) as an orange solid, which was usedwithout further purification in the next step; Rt 2.11 min (method 1);m/z 395 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-(1-(methylsulfonyl)piperidin-4-yl)benzene-1,2-diamine(C10)

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)piperidin-4-amine(3.34 g, 8.47 mmol) was dissolved in water (200 mL) and THF (200 mL).Concentrated ammonia (6.59 ml, 169 mmol) and sodium dithionite (14.74 g,85 mmol) were added and the reaction stirred at RT for 2 h. EtOAc (500ml) was added, the mixture transferred to a sep funnel and washedsequentially with 1M NaOH (400 ml) and brine (200 ml). The organic phasewas passed through a phase sep cartridge and concentrated in vacuo toafford4-(3,5-dimethylisoxazol-4-yl)-N1-(1-(methylsulfonyl)piperidin-4-yl)benzene-1,2-diamine(1.97 g, 4.97 mmol, 58.7% yield) as an off white foam; Rt 1.35 min(method 1); m/z 365 (M+H)+ (ES+).

(1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentan-1-ol(B11)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.14 g, 4.84 mmol),(1r,3r)-3-aminocyclopentanol hydrochloride (1.0 g, 7.27 mmol) and TEA(2.4 mL, 16.96 mmol) were heated to reflux in THF (17.47 mL, 213 mmol)for 18 h. The mixture was cooled to RT and concentrated invacuo/pre-adsorbed onto silica. Purification by flash chromatography onthe Companion (40 g column, 50-100% EtOAc/isohexane) afforded(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol(0.66 g, 40%) as an orange solid; Rt 1.94 min (method 1); m/z 318 (M+H)+(ES+).

(1R,3R)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclopentan-1-ol(C11)

(1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol(0.66 g, 2.080 mmol) and concentrated ammonia (1.296 ml, 33.3 mmol) weredissolved in THF/water (40 mL). Sodium dithionite (3.62 g, 20.80 mmol)was added and the reaction mixture stirred at RT for 1.5 h. EtOAc (200mL) was added, the mixture transferred to a separating funnel and washedsequentially with 1M NaOH (50 mL) and brine (100 mL). The organic phasewas passed through a PhaseSep© cartridge and concentrated in vacuo toafford(1R,3R)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclopentanol(0.45 g, 1.535 mmol, 73.8% yield) as a purple solid; Rt 1.06 min (method1); m/z 288 (M+H)+ (ES+).

N-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(B12)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (4.0 g, 16.77 mmol),4,4-difluorocyclohexanamine hydrochloride (3.0 g, 17.48 mmol) andpotassium carbonate (7.0 g, 50.6 mmol) were heated to reflux inacetonitrile (60 mL) for 2 h. 4,4-Difluorocyclohexanamine hydrochloride(3.0 g, 17.48 mmol) and potassium carbonate (7.0 g, 50.6 mmol) wereadded and the mixture was heated for a further 4 h. The mixture wascooled then diluted with water (200 mL) and filtered to yieldN-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(5.85 g, 98%) as an orange crystalline solid; Rt 1.67 min (method 1);m/z 352 (M+H)+ (ES+).

N¹-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(C12)

Sodium dithionite (38.5 g, 188 mmol) was added to a mixture ofN-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(5.85 g, 16.48 mmol), concentrated ammonia (15 ml, 385 mmol), THF/water(1:1, 120 ml) then stirred at room temperature for 2.5 h. The mixturewas diluted with water (250 mL) then filtered to yieldN¹-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(4.1 g, 70% yield); Rt 1.27 min (method 1); m/z 322 (M+H)+ (ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-methyltetrahydro-2H-pyran-4-amine(B13)

A solution of 2-methyltetrahydro-2H-pyran-4-amine (1.024 g, 8.89 mmol),DIPEA (2.59 ml, 14.82 mmol) and4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.75 g, 7.41 mmol) inTHF (40 mL) was heated at reflux for 24 h. The reaction mixture wasconcentrated in vacuo/pre-adsorbed onto silica. The crude product waspurified by chromatography on silica gel (40 g column, 0-50%EtOAc/isohexane) to affordN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-methyltetrahydro-2H-pyran-4-amine(1.76 g, 71%) as a yellow solid; Rt 2.27 min (method 1); m/z 332 (M+H)+(ES+). The product was analysed by LCMS (Agilent, X-Select, WatersX-Select C18, 2.5 μm, 4.6×30 mm, Acidic (0.1% Formic acid) 4 min method,5-95% MeCN/water): 1576-41-P, m/z 332.2 (M+H)+ (ES+); at 2.27 min, 99%purity @ 254 nm. ¹H NMR (d₆-DMSO) was consistent with product structureas a 9:1 mixture of diastereomers.

4-(3,5-dimethylisoxazol-4-yl)-N¹-(2-methyltetrahydro-2H-pyran-4-yl)benzene-1,2-diamine(C13)

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-methyltetrahydro-2H-pyran-4-amine(1.66 g, 5.01 mmol) was dissolved in THF (71.0 ml, 867 mmol), Water(68.2 ml, 3787 mmol), ammonia (3.90 ml, 100 mmol) and sodium dithionite(8.72 g, 50.1 mmol) added and the reaction stirred at RT for 2 h. Thelayers were separated and the aqueous was extracted with EtOAc (2×20mL), the combined organics washed with brine (20 mL), dried (MgSO₄),filtered and evaporated in vacuo to give4-(3,5-dimethylisoxazol-4-yl)-N¹-(2-methyltetrahydro-2H-pyran-4-yl)benzene-1,2-diamine(1.45 g, 85% yield) as a yellow oil; Rt 1.55 min (method 1); m/z 302(M+H)+ (ES+); ¹H NMR (d₆-DMSO) was consistent with product structure asa 9:1 mixture of diastereomers.

4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one(B14)

To a solution of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.3g, 5.50 mmol) in tetrahydrofuran (26.6 mL) and DIPEA (1.923 ml, 11.01mmol) was added 4-aminopiperidin-2-one (0.942 g, 8.26 mmol). Thereaction stirred at 70° C. for 48 h. The reaction was cooled down to RT.The solvents were evaporated in vacuo and the orange residue waspartitioned between EtOAc (100 mL), DCM (100 mL) and saturated aqueousNaHCO₃ (100 mL) and the layers separated. The aqueous phase wasextracted with further DCM (2×100 mL) and the combined organic extractswashed with water (100 mL) and brine (100 mL). The solution was dried(MgSO₄), filtered and evaporated in vacuo. The residual orange solid waspurified by chromatography on the Companion (24 g column, 0-100% EtOAcin DCM then 0-10% MeOH in DCM, loaded on silica) to give4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one(1.0 g, 54%) as an orange foam; Rt 1.66 min (method 1); m/z 331 (M+H)+(ES+).

4-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidin-2-one(C14)

4-((4-(3,5-Dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one(1.0 g, 3.03 mmol) and concentrated ammonia (1.886 mL, 48.4 mmol) weredissolved in THF/water (1:1, 58 mL). Sodium dithionate (6.24 g, 30.3mmol) was added and the reaction mixture stirred at RT. After 1 h ofstirring, the layers were separated, the aqueous extracted with EtOAc(100 mL) and the combined organics washed with brine (50 mL), dried(MgSO₄), filtered and evaporated in vacuo to give4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidin-2-one(0.67 g, 71%) as a white solid; Rt 1.41 min (method 1); m/z 301 (M+H)+(ES+).

(1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexan-1-ol(B15)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (750 mg, 3.18 mmol),(1s,4s)-4-amino-1-methylcyclohexanol (500 mg, 3.87 mmol) and potassiumcarbonate (600 mg, 4.34 mmol) were heated to reflux in acetonitrile (10mL) for 1 h. The mixture was diluted with water (50 mL) then theprecipitate was collected by filtration. The crude product was purifiedby chromatography on the Companion (40 g column, 0-50% EtOAc/isohexane)to afford(1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexanol(855 mg, 74%) as an orange solid; Rt 2.15 min (method 1); m/z 346 (M+H)+(ES+).

(1s,4s)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexan-1-ol(C15)

Sodium dithionite (5 g, 24.41 mmol) was added to a mixture of(1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexanol(844 mg, 2.444 mmol), concentrated ammonia (2 ml, 51.4 mmol), THF/water(1:1 12 mL) then stirred at room temperature for 3 h. The mixture wasdiluted with brine (100 mL) then extracted with ethyl acetate (3×150mL), then dichloromethane (2×50 mL). The combined organic phases wereconcentrated under reduced pressure. The residue was stirred in ethanol(15 mL) and water (35 mL) with sodium bicarbonate (205 mg, 2.444 mmol)for 15 minutes. The solid was collected by filtration to yield(1s,4s)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexanol(574 mg, 73%) as a pink solid; Rt 1.28 min (method 1); m/z 316 (M+H)+(ES+).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan-6-amine(B16)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.435 g, 6.08 mmol)and 2-oxaspiro[3.3]heptan-6-amine hydrochloride (1 g, 6.68 mmol) wasdissolved in dry dimethylformamide (20 mL). TEA (2.54 mL, 18.23 mmol)was added and the reaction warmed to 60° C. and left to stir at rt for 3h. After cooling to RT, the reaction mixture was poured into ice water(100 mL), then extracted with ethyl acetate (2×100 mL). Combinedorganics were dried (MgSO₄) and concentrated in vacuo then azeotropingwith acetonitrile to affordN-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan-6-amine(2.58 g, >100% yield) as an orange solid, which was used without furtherpurification at the next step; Rt 2.14 min (method 1); m/z 330 (M+H)+(ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-(2-oxaspiro[3.3]heptan-6-yl)benzene-1,2-diamine(C16)

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan-6-amine(2.00 g, 6.07 mmol) was dissolved in a mixture of THF/water (1:1, 300mL). Sodium dithionite (10.57 g, 60.7 mmol) was added followed byconcentrated ammonia (4.73 ml, 121 mmol) and the reaction mixturestirred at RT for 10 mins. EtOAc (200 mL) was added, the mixturetransferred to a separating funnel and washed sequentially with 1M NaOH(100 mL) and brine (100 mL). The organic phase was passed through aPhaseSep© cartridge and concentrated in vacuo to afford4-(3,5-dimethylisoxazol-4-yl)-N¹-(2-oxaspiro[3.3]heptan-6-yl)benzene-1,2-diamine(1.47 g, 4.76 mmol, 78% yield) as a light pink solid; Rt 1.35 min(method 1); m/z 300 (M+H)+ (ES+).

(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobutan-1-ol(B17)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (8.69 g, 36.8 mmol) wasdissolved in dry dimethylformamide (50 mL) and TEA (20.51 mL, 147 mmol).(1r,3r)-3-aminocyclobutanol hydrochloride (5 g, 40.5 mmol) was added andthe reaction warmed to 60° C. and left to stir at RT for 18 h. Aftercooling to rt the reaction mixture was poured into ice water (300 mL)The precipitate was collected to afford(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobutanol(11.16 g, 98%) as an orange solid; Rt 1.89 min (method 1); m/z 304(M+H)+ (ES+).

(1r,3r)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclobutan-1-ol(C17)

(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobutanol(11.16 g, 36.8 mmol) was dissolved in a mixture of THF/water (1:1, 800mL). Sodium dithionate (64.1 g, 368 mmol) was added followed byconcentrated ammonia, 28% soln (28.7 mL, 736 mmol) and the reactionmixture stirred at RT for 18 h. EtOAc (1 L) was added, followed by 1MNaOH (500 mL). After stirring for 5 mins, the layers were left toseparated and the aqueous phase removed. The organic phase was stirredvigorously with brine (500 mL), left to separate, then collected anddried (MgSO₄). The solvent was removed in vacuo and the residuetriturated with ether (200 mL) to afford(1r,3r)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclobutanol(7.07 g, 70%) as a beige solid; Rt 1.09 min (method 1); m/z 274 (M+H)+(ES+).

(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexan-1-ol(B18)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.618 g, 6.85 mmol),(1r,4r)-4-amino-1-methylcyclohexanol (1.0 g, 7.74 mmol) and potassiumcarbonate (1.638 g, 11.85 mmol) were heated to reflux in acetonitrile(20.75 mL) for 1 h. The reaction was cooled down to RT and stirredovernight. The mixture was diluted with water (200 mL) then the orangeprecipitate was collected by filtration. The crude product (ca. 4 g as awet solid) was purified by chromatography on the Companion (24 g column,0-50% EtOAc/DCM) to afford(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexanol(2.0 g, 79%) as an orange solid; Rt 2.10 min (method 1); m/z 346 (M+H)+(ES+).

(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexan-1-ol(C18)

Sodium dithionite (11.10 g, 53.9 mmol) was added to a mixture of(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexanol(2.0 g, 5.39 mmol), concentrated ammonia (4.09 ml, 105 mmol), THF/water(1:1, 32.6 mL) then stirred at RT. The volume of solvent was doubledbecause of poor solubility. After 2 h, the layers were separated, theaqueous extracted with EtOAc (2×100 mL), the combined organics washedwith water (50 mL) and brine (50 mL), dried (MgSO₄), filtered andevaporated in vacuo to give (1_(r),4_(r))-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexanol(1.45 g, 82%) as a pink purple solid; Rt 1.10 min (method 1); m/z 316(M+H)+ (ES+).

1-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)propan-2-ol (B19)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (4 g, 16.93 mmol) wasdissolved in dry THF (69.4 mL, 847 mmol) and TEA (7.08 mL, 50.8 mmol).1-aminopropan-2-ol (1.438 mL, 18.63 mmol) was added and the reactionwarmed to 60° C. and left to stir at RT for 18 h. After cooling to RTthe reaction mixture was poured into ice water (300 mL) and extractedwith EtOAc (2×75 mL). The organic extracts were combined and then driedover MgSO₄, filtered and concentrated in vacuo to afford a1-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)propan-2-ol (4.90g, 98%) as a yellow solid; Rt 1.85 min (method 1); m/z 292 (M+H)+ (ES+).

1-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)propan-2-ol (C19)

1-((4-(3,5-Dimethylisoxazol-4-yl)-2-nitrophenyl)amino)propan-2-ol (4.9g, 16.82 mmol) was dissolved in a mixture of THF/water (1:1 132 mL).Sodium dithionite (34.5 g, 168 mmol) was added followed by concentratedammonia (13.10 ml, 336 mmol) and the reaction mixture stirred at RT for1 h. EtOAc (200 mL) was added, the mixture transferred to a sep funneland washed sequentially with 1M NaOH (100 mL) and brine (100 mL). Theorganic phase was passed through a PhaseSep© cartridge and concentratedin vacuo to afford1-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)propan-2-ol (3.7g, 78%) as a red solid; Rt 2.10 min (method 1); m/z 262 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (B20)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (10 g,42.3 mmol) and 2-methylpropan-1-amine (21.04 mL, 212 mmol) was stirredin dry THF (100 mL) and the reaction was stirred at RT for 18 h thenpoured into ice water (300 mL). The mixture was extracted with ethylacetate (2×500 mL). Combined organics were dried (MgSO₄) andconcentrated in vacuo to afford4-(3,5-dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (12.25 g, 100%)as an orange solid; Rt 2.64 min (method 1); m/z 290 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N1-isobutylbenzene-1,2-diamine (C20)

4-(3,5-Dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (12.25 g, 42.3mmol) was dissolved in a mixture of THF/water (1:1, 800 mL). Sodiumdithionite (73.7 g, 423 mmol) was added followed by concentrated ammonia(33.0 mL, 847 mmol) and the reaction mixture stirred at RT for 18 h.EtOAc (1 L) was added, followed by 1M NaOH (500 mL). After stirring for5 mins, the layers were left to separate and the aqueous phase removed.The organic phase was stirred vigorously with brine (500 mL), left toseparate, then collected and dried (MgSO₄). The solvent was removed invacuo and the residue triturated with ether (200 mL) to afford4-(3,5-dimethylisoxazol-4-yl)-N¹-isobutylbenzene-1,2-diamine as a beigesolid; Rt 1.09 min (method 1); m/z 274 (M+H)+ (ES+).

N-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(B21)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.870 g, 7.92 mmol)and 3,3-difluorocyclobutanamine hydrochloride (1.25 g, 8.71 mmol) wasdissolved in dry dimethylformamide (20 ml). TEA (3.31 ml, 23.75 mmol)was added and the reaction warmed to 60° C. and left to stir at rt for 3h. After cooling to rt the reaction mixture was poured into ice water(100 ml), then extracted with ethyl acetate (2×100 ml). Combinedorganics were dried (MgSO4) and concentrated in vacuo (azeotroping withacetonitrile) to affordN-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(2.11 g, 5.94 mmol, 75% yield) as an orange solid; Rt 2.42 min (method1); m/z 324 (M+H)+ (ES+).

N¹-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(C21)

N-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(2.10 g, 6.50 mmol) was dissolved in a mixture of THF/water (1,1, 200mL). Sodium dithionate (11.31 g, 65.0 mmol) was added followed byconcentrated ammonia (5.06 ml, 130 mmol) and the reaction mixturestirred at RT for 1 hr. EtOAc (200 mL) was added, followed by 1M NaOH(150 mL). The mixture was shaken vigorously and the aqueous phasediscarded. The organic phase was washed with brine (100 mL), thencollected and dried (MgSO₄). The solvent was removed in vacuo to affordN¹-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(1.12 g, 58%) as an-off white solid; Rt 1.84 min (method 1); m/z 294(M+H)+ (ES+).

Methyl(1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexane-1-carboxylate(B22)

To a suspension of (1r,4r)-methyl 4-aminocyclohexanecarboxylatehydrochloride (3.4 g, 17.56 mmol) and DIPEA (7.67 mL, 43.9 mmol) inacetonitrile (68.8 mL) was added4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (4.56 g, 19.31 mmol).The heterogeneous reaction was stirred at 75° C. for 39 h. The reactionwas cooled down to RT and filtered. The filtrate was concentrated invacuo to give a mixture of oil and orange solid (11 g). The solid wastriturated twice with Et₂O (50 mL), then iso-hexanes (50 mL). The solidwas dried in vacuo to give 7.5 g of solid which was dried loaded andpurified by chromatography column (120 g, DCM/MeOH: 100/0 to 95/5) togive (1r,4r)-methyl4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanecarboxylate(4.29 g, 63%) was isolated as an orange solid; Rt 2.49 min (method 1);m/z 374 (M+H)+ (ES+).

Methyl(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexane-1-carboxylate(C22)

Sodium dithionite (23.68 g, 115 mmol) was added to a mixture of(1r,4r)-methyl4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanecarboxylate(4.29 g, 11.49 mmol), concentrated ammonia (8.72 ml, 224 mmol), water(34.8 mL) and THF (43.3 mL) then stirred at room temperature for 15 h.The layers were separated, the aqueous extracted with EtOAc (2×100 mL),the combined organics washed with water (2×100 mL) and brine (100 mL),dried (MgSO₄), filtered and evaporated in vacuo to give(1r,4r)-methyl-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanecarboxylate (3.52 g, 87%) as a crude pink red solid; Rt 1.49min (method 1); m/z 344 (M+H)+ (ES+).

(R)—N¹-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(B23)

EXAMPLES Example 1:5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-oneN-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide

HATU (110 mg, 0.289 mmol) was added to a solution of Intermediate C1(100 mg, 0.254 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (55mg, 0.268 mmol) and N,N-diisopropylethylamine (55 μL, 0.315 mmol) inN,N-dimethylformamide (2 mL) then stirred at room temperature overnight.The mixture was diluted with water (20 mL) then extracted with ethylacetate (2×20 mL). The combined organic phases were washed with 20%brine (2×20 mL), saturated brine (20 mL), then dried (MgSO₄), filteredand concentrated under reduced pressure. The crude product was purifiedby chromatography on the Companion (12 g column, 50-100% EtOAc/DCM) toaffordN-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(87 mg, 63%) as a colourless foam; Rt 1.78 min (method 1); m/z 538(M+H)+ (ES+).

5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one

N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(135 mg, 0.251 mmol) was heated to 80° C. in acetic acid (3 mL) over 2.5days. The volatiles were removed under reduced pressure then the residuewas purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid),Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 15-40% MeCN inWater) to afford5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(15 mg, 11%) as a colourless glass; Rt 1.77 min 2 (method 1); m/z 520(M+H)+ (ES+); 1H NMR in DMSO-d6 7.75 (dt, J=8.4, 0.9 Hz, 1H), 7.65 (dd,J=1.6, 0.6 Hz, 1H), 7.55-7.46 (m, 2H), 7.31 (ddd, J=8.8, 7.3, 1.8 Hz,2H), 7.25 (dd, J=8.5, 1.8 Hz, 1H), 7.09 (tq, J=7.6, 1.0 Hz, 1H), 6.06(dd, J=8.2, 2.3 Hz, 1H), 5.59-5.46 (m, 1H), 3.83-3.58 (m, 3H), 3.47-3.36(m, 1H), 3.09 (s, 3H), 2.82-2.47 (m, 4H), 2.42-2.30 (m, 1H), 2.38 (s,3H), 2.28-2.14 (m, 1H), 2.21 (s, 3H).

Example 2:5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-oneN-(5-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide

HATU (125 mg, 0.329 mmol) was added to a solution of Intermediate C2 (99mg, 0.331 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (70 mg,0.341 mmol) and N,N-diisopropylethylamine (70 μl, 0.401 mmol) inN,N-dimethylformamide (2 mL) then stirred at room temperature over aweekend. The mixture was added dropwise to a rapidly stirred flask ofwater (20 mL) then the precipitate was collected by filtration, washingwith water (2×3 mL) to yieldN-(5-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(121 mg, 69%) as a red-orange gum; Rt 1.17 min 2 (method 1); m/z 475(M+H)+ (ES+);

5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one

N-(5-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide (121 mg, 0.227 mmol) was heated to 80° C. inpivalic acid (3 mL) for 2 h. 1,4-dioxane (3 mL) was added to improvesolubility then the mixture was heated at 80° C. for a further 3 h. Thetemperature was increased to 100° C. and stirred for 18 h. The mixturewas diluted with water (20 mL) then extracted with dichloromethane (3×10mL). The combined organic phases were concentrated under reducedpressure then purified by chromatography on the Companion (RP Flash C18)(12 g column, 15-75% MeCN/Water 0.1% Formic Acid) to afford5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(18 mg, 16%) as an off-white solid; Rt 1.77 min (method 1); m/z 457(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6Hz, 1H), 7.51-7.45 (m, 2H), 7.29 (dd, J=8.6, 7.4 Hz, 2H), 7.17 (dd,J=8.5, 1.7 Hz, 1H), 7.11-7.04 (m, 1H), 6.10 (dd, J=8.3, 2.2 Hz, 1H),4.87-4.74 (m, 1H), 4.04 (td, J=14.2, 12.9, 4.3 Hz, 2H), 3.57 (ddd,J=12.3, 9.6, 3.3 Hz, 2H), 2.85-2.72 (m, 1H), 2.65 (dq, J=12.0, 8.8 Hz,1H), 2.59-2.51 (m, 1H), 2.43 (td, J=12.3, 4.6 Hz, 2H), 2.36 (s, 3H),2.19 (s, 3H), 2.18-2.09 (m, 1H), 1.81 (d, J=12.6 Hz, 1H), 1.58 (d,J=12.5 Hz, 1H).

Example 3:5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-oneN-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide

HATU (125 mg, 0.329 mmol) was added to a solution of Intermediate C3 (99mg, 0.269 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (70 mg,0.341 mmol) and N,N-diisopropylethylamine (70 μl, 0.401 mmol) inN,N-dimethylformamide (2 mL) then stirred at room temperature over aweekend. The mixture was added dropwise to a rapidly stirred flask ofwater (20 mL) then the precipitate was collected by filtration, washingwith water (2×3 mL) to yieldN-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(135 mg, 92%) as an off white solid; Rt 1.07 min (method 1), m/z 523(M+H)+ (ES+).

5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one

N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(135 mg, 0.248 mmol) was heated to 80° C. in pivalic acid (3 mL). for 2h. 1,4-dioxane (3 mL) was added to improve solubility then the mixturewas heated at 80° C. for a further 3 h. The temperature was increased to100° C. and stirred for 18 h, further heated for 3 h at 160° C. usingmicrowave heating and then for a further 4 h at 180° C. using microwaveheating. The solvents were removed under reduced pressure then the crudeproduct was purified by chromatography on the Companion (RP Flash C18)(12 g column, 15-75% MeCN/Water 0.1% Formic Acid) to afford5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(37 mg, 28%) as a pale cream solid; Rt 1.69 min (method 1), m/z 505(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.65 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.5Hz, 1H), 7.53-7.45 (m, 2H), 7.34-7.25 (m, 3H), 7.10 (dt, 1H), 5.97 (d,J=7.1 Hz, 1H), 5.12-4.95 (m, 1H), 3.63-3.51 (m, 2H), 3.31-3.21 (m, 2H),2.96-2.53 (m, 5H), 2.38 (s, 3H), 2.29-2.14 (m, 2H), 2.21 (s, 3H), 1.97(br d, J=13.5 Hz, 1H).

Example 4:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D1)

HATU (350 mg, 0.920 mmol) was added to a solution of Intermediate C1(300 mg, 0.822 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (120 mg,0.929 mmol) and N,N-diisopropylethylamine (175 l, 1.002 mmol) inN,N-dimethylformamide (5 mL) then stirred at room temperature for 2 h.The mixture was diluted with water (40 mL) then extracted with ethylacetate (3×20 mL). The combined organic phases were washed with 20%brine (2×20 mL), saturated brine (20 mL), then dried (MgSO₄), filteredand concentrated under reduced pressure to yield(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (293 mg, 66%) as a red-brown gum; Rt 1.45 min(method 1), m/z 462 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E1)

Intermediate D1 (293 mg, 0.546 mmol) was heated to 80° C. in acetic acid(5 mL) for 6 h. The mixture was concentrated under reduced pressure thendiluted with water (40 mL) and extracted with ethyl acetate (3×20 mL).The combined organic phases were washed with 20% brine (2×20 mL),saturated brine (20 mL), then dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude product was purified by chromatographyon the Companion (12 g column, 15-75% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(99 mg, 41%) as a tan solid; Rt 0.84 min (method 1), m/z 444 (M+H)+(ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one

DBU (11 μL, 0.073 mmol) was added to a solution of Intermediate E1 (30mg, 0.068 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (5 mg, 10.77 μmop was added and the suspension was stirred for afurther 2 minutes before adding phenylboronic acid (10 mg, 0.082 mmol)and stirring for 18 h. The mixture was concentrated under reducedpressure then purified by chromatography on the Companion (12 g column,15-75% acetone/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(12 mg, 33%) as a pale yellow solid; Rt 1.75 min (method 1), m/z 520(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.79-7.70 (m, 1H), 7.70-7.60 (m, 1H),7.50 (dd, J=8.7, 1.2 Hz, 2H), 7.31 (dd, J=8.6, 7.4 Hz, 2H), 7.25 (dd,J=8.4, 1.7 Hz, 1H), 7.13-7.05 (m, 1H), 6.06 (dd, J=8.2, 2.3 Hz, 1H),5.59-5.44 (m, 1H), 3.83-3.55 (m, 3H), 3.43-3.36 (m, 1H), 3.09 (s, 3H),2.83-2.54 (m, 3H), 2.49-2.43 (m, 1H), 2.41-2.30 (m, 1H), 2.38 (s, 3H),2.26-2.16 (m, 1H), 2.21 (s, 3H). Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=9.36 min, 96%, 92% de @ 254 nm.

Example 5:(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

HATU (225 mg, 0.592 mmol) was added to a solution of Intermediate C1(200 mg, 0.548 mmol), (R)-5-oxopyrrolidine-2-carboxylic acid (75 mg,0.581 mmol) and N,N-diisopropylethylamine (110 μl, 0.630 mmol) inN,N-dimethylformamide (3 mL) then stirred at room temperature for 18 h.The mixture was diluted with water (15 mL) then extracted with ethylacetate (3×15 mL). The combined organic phases were washed with 20%brine (2×20 mL), saturated brine (20 mL), then dried (MgSO₄), filteredand concentrated under reduced pressure to yield(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(253 mg, 0.548 mmol, 100% yield) as a red-brown gum; Rt 1.45 min (method1), m/z 462 (M+H)+ (ES+).

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E23)

(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(253 mg, 0.548 mmol) was heated to 80° C. in acetic acid (3 mL) for 5 h.The solvent was removed under reduced pressure then diluted with water(40 mL) and extracted with ethyl acetate (3×20 mL). The combined organicphases were washed with 20% brine (2×20 mL), saturated brine (20 mL),then dried (MgSO₄), filtered and concentrated under reduced pressure.The crude product was purified by flash chromatography on the Companion(12 g column, 15-75% MeAc/DCM) to afford(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(71 mg, 0.158 mmol, 28.9% yield) as an off white solid. Rt 1.33 min(method 1), m/z 444 (M+H)+ (ES+).

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one

DBU (25 μL, 0.166 mmol) was added to a solution of(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(70 mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding phenylboronic acid (20 mg, 0.164 mmol)and stirring for 18 h. The mixture was concentrated under reducedpressure then purified by chromatography on the Companion (4 g column,0-50% MeAc/DCM) to afford(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(18 mg, 22%) as an off white solid; Rt 1.78 min (method 1), m/z 520(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78-7.72 (m, 1H), 7.69-7.62 (m, 1H),7.56-7.45 (m, 2H), 7.30 (dd, J=8.6, 7.3 Hz, 2H), 7.25 (dd, J=8.4, 1.7Hz, 1H), 7.13-7.05 (m, 1H), 6.11-5.99 (m, 1H), 5.60-5.44 (m, 1H), 3.72(ddd, J=11.1, 8.6, 2.9 Hz, 2H), 3.63 (dd, J=10.5, 6.8 Hz, 1H), 3.47-3.36(m, 1H), 3.10 (s, 3H), 2.79-2.59 (m, 2H), 2.59-2.40 (m, 3H), 2.38 (s,3H), 2.21 (s, 3H), 2.20-2.10 (m, 1H). Chiral HPLC (Diacel Chiralpak IA,5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=10.49 min, 99.8%, 99.6% de @ 254 nm.

Example 6:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one

A solution of DBU (25 μL, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-fluorophenyl)boronic acid (25 mg, 0.179 mmol)before stirring for 18 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (4 gcolumn, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one (30 mg, 34% yield) as an off white solid; Rt 1.85 min(method 1), m/z 538 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=8.4 Hz,1H), 7.65 (d, J=1.6 Hz, 1H), 7.61 (dt, J=11.9, 2.3 Hz, 1H), 7.34 (td,J=8.3, 6.9 Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 7.22 (ddd, J=8.4, 2.1,0.9 Hz, 1H), 6.93 (tdd, J=8.4, 2.5, 0.9 Hz, 1H), 6.12 (dd, J=8.1, 1.9Hz, 1H), 5.62-5.46 (m, 1H), 3.95-3.61 (m, 3H), 3.47-3.36 (m, 1H), 3.10(s, 3H), 2.81-2.52 (m, 5H), 2.37 (s, 3H), 2.21 (s, 3H), 2.19-2.13 (m,1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method,1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=8.38 min,93%, 86% de @ 254 nm.

Example 7:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-difluorophenyl)boronic acid (25 mg, 0.158mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(43 mg, 0.074 mmol, 47.1% yield) as an off-white solid; Rt 1.92 min(method 1), m/z 556 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.83 (ddd, J=13.3,7.4, 2.7 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.39(dt, J=10.6, 9.2 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 7.24-7.16 (m,1H), 6.16-6.02 (m, 1H), 5.58-5.44 (m, 1H), 3.88-3.61 (m, 3H), 3.45-3.35(m, 1H), 3.10 (s, 3H), 2.78-2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H),2.20-2.13 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=6.78 min, 93%, 86% de @ 254 nm.

Example 8:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μL, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (4-chloro-3-fluorophenyl)boronic acid(30 mg, 0.172 mmol) and stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(39 mg, 41%) as an off-white solid; Rt 2.05 min (method 1), m/z 572(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.85 (dd, J=12.1, 2.5 Hz, 1H),7.81-7.74 (m, 1H), 7.64 (dd, J=1.6, 0.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H),7.30-7.23 (m, 2H), 6.18-6.08 (m, 1H), 5.58-5.46 (m, 1H), 3.87-3.63 (m,3H), 3.46-3.36 (m, 1H), 3.10 (s, 3H), 2.77-2.52 (m, 5H), 2.37 (s, 3H),2.20 (s, 3H), 2.19-2.12 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 mm,4.6×250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=7.75 min, 86%, 73% de @ 254 nm.

Example 9:(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (3-chloro-4-fluorophenyl)boronic acid(30 mg, 0.172 mmol) and stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(44 mg, 0.073 mmol, 46.8% yield) as an off white solid; Rt 2.07 min(method 1), m/z 572 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.95 (dd, J=6.9,2.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.44-7.33(m, 2H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 6.17-6.06 (m, 1H), 5.56-5.49 (m,1H), 3.86-3.62 (m, 3H), 3.44-3.36 (m, 1H), 3.10 (s, 3H), 2.79-2.52 (m,5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.20-2.12 (m, 1H). Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=6.89 min, 93%, 86% de @ 254 nm.

Example 10:(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μL, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (3,5-dichlorophenyl)boronic acid (35mg, 0.183 mmol) and stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (40 mg, 0.065 mmol, 41.3% yield) as an off-white solid;Rt 2.18 min (method 1), m/z 588 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ:7.83-7.75 (m, 1H), 7.69 (d, J=1.9 Hz, 2H), 7.66 (dd, J=1.6, 0.5 Hz, 1H),7.34 (t, J=1.8 Hz, 1H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 6.29-6.17 (m, 1H),5.60-5.49 (m, 1H), 3.88-3.65 (m, 3H), 3.40 (q, J=9.4, 9.0 Hz, 1H), 3.10(s, 3H), 2.82-2.53 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.17 (d, J=9.9Hz, 1H). Chiral HPLC (Lab 1 Bay 4, Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=7.02 min, 90%, 80% de @ 254 nm.

Example 11:(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-5-fluorophenyl)boronic acid (30 mg,0.172 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(40 mg, 42%) as an off-white solid; Rt 2.08 min (method 1), m/z 572(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.66 (dd,J=1.7, 0.6 Hz, 1H), 7.57 (dt, J=2.4, 1.2 Hz, 1H), 7.49 (dt, J=11.4, 2.2Hz, 1H), 7.27 (dd, J=8.4, 1.7 Hz, 1H), 7.18 (dt, J=8.5, 2.1 Hz, 1H),6.23-6.15 (m, 1H), 5.59-5.47 (m, 1H), 3.88-3.66 (m, 3H), 3.40 (q, J=9.0Hz, 1H), 3.10 (s, 3H), 2.79-2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H),2.19-2.12 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=7.10 min, 89%, 78% de @ 254 nm.

Example 12:(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (3-chloro-5-methoxyphenyl)boronic acid(33 mg, 0.177 mmol) and stirring for 2 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(39 mg, 40%) as an off white solid; Rt 2.02 min (method 1), m/z 584(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (dd, J=8.5, 0.6 Hz, 1H), 7.65(dd, J=1.7, 0.6 Hz, 1H), 7.33 (t, J=1.9 Hz, 1H), 7.26 (dd, J=8.4, 1.7Hz, 1H), 7.06 (t, J=2.1 Hz, 1H), 6.78 (t, J=2.0 Hz, 1H), 6.19-6.08 (m,1H), 5.61-5.51 (m, 1H), 3.86-3.64 (m, 3H), 3.69 (s, 3H), 3.40 (td,J=9.6, 7.3 Hz, 1H), 3.09 (s, 3H), 2.82-2.52 (m, 5H), 2.38 (s, 3H), 2.21(s, 3H), 2.19-2.11 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=8.44 min, 94%, 88% de @ 254 nm.

Example 13:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

DBU (25 μL, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (3-fluoro-4-methoxyphenyl)boronic acid(30 mg, 0.177 mmol) and stirring for 2 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (52 mg, 56%) as an off white solid; Rt 1.83 min(method 1), m/z 568 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.76 (dd, J=8.5,0.7 Hz, 1H), 7.65 (dd, J=1.7, 0.6 Hz, 1H), 7.64-7.55 (m, 1H), 7.25 (dd,J=8.4, 1.7 Hz, 1H), 7.14-7.03 (m, 2H), 6.02 (dd, J=8.2, 2.3 Hz, 1H),5.56-5.46 (m, 1H), 3.86-3.62 (m, 3H), 3.76 (s, 3H), 3.44-3.33 (m, 1H),3.09 (s, 3H), 2.79-2.53 (m, 4H), 2.45-2.38 (m, 1H), 2.38 (s, 3H), 2.21(s, 3H), 2.20-2.12 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=9.72 min, 94%, 88% de @ 254 nm.

Example 14:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of Intermediate E1 (70mg, 0.156 mmol) in acetonitrile (5 mL) then stirred for 5 minutes.CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred fora further 2 minutes before adding (3-chloro-4-methoxyphenyl)boronic acid(33 mg, 0.177 mmol) and stirring for 2 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/CH2Cl2) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(42 mg, 44%) as an off white solid; Rt 1.91 min (method 1), m/z 584(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=2.6 Hz, 1H), 7.76-7.73 (m,1H), 7.66 (dd, J=1.7, 0.6 Hz, 1H), 7.30 (dd, J=9.0, 2.6 Hz, 1H), 7.25(dd, J=8.4, 1.7 Hz, 1H), 7.08 (d, J=9.1 Hz, 1H), 6.05 (dd, J=8.2, 2.4Hz, 1H), 5.57-5.47 (m, 1H), 3.84-3.60 (m, 3H), 3.78 (s 3H), 3.38 (td,J=9.6, 7.2 Hz, 1H), 3.09 (s, 3H), 2.80-2.52 (m, 4H), 2.42-2.32 (m, 1H),2.38 (s, 3H), 2.24-2.16 (m, 1H), 2.21 (s, 3H). Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=9.55 min, 94%, 88% de @ 254 nm.

Example 15:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)pyrrolidin-2-one

A solution of DBU (25 μL, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-methoxyphenyl)boronic acid (28 mg, 0.184mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)pyrrolidin-2-one (54 mg, 60%) as an off white solid; Rt 1.75 min (method1), m/z 550 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H),7.66 (d, J=1.6 Hz, 1H), 7.41-7.33 (m, 2H), 7.24 (dd, J=8.4, 1.7 Hz, 1H),6.91-6.81 (m, 2H), 5.97 (dd, J=8.2, 2.7 Hz, 1H), 5.52-4.42 (m, 1H),3.82-3.49 (m, 3H), 3.68 (s, 3H), 3.39-3.28 (m, 1H), 3.08 (s, 3H),2.82-2.52 (m, 3H), 2.50-2.40 (m, 1H), 2.38 (s, 3H), 2.27-2.17 (m, 2H),2.22 (s, 3H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=10.41min, 95.7%, 91.4% de @ 254 nm.

Example 16(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-propoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-propoxyphenyl)pyrrolidin-2-one

A solution of DBU (25 μL, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-propoxyphenyl)boronic acid (32 mg, 0.178mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-propoxyphenyl)pyrrolidin-2-one (56 mg, 59%) as an off white solid; Rt 2.00 min (method1), m/z 578 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H),7.66 (d, J=1.6 Hz, 1H), 7.39-7.31 (m, 2H), 7.24 (dd, J=8.5, 1.7 Hz, 1H),6.90-6.82 (m, 2H), 5.96 (dd, J=8.2, 2.7 Hz, 1H), 5.52-5.42 (m, 1H), 3.84(t, J=6.6 Hz, 2H), 3.75 (dd, J=10.6, 8.9 Hz, 1H), 3.68 (td, J=9.5, 8.5,2.5 Hz, 1H), 3.60 (dd, J=10.6, 6.8 Hz, 1H), 3.40-3.29 (m, 1H), 3.08 (s,3H), 2.83-2.52 (m, 3H), 2.47-2.40 (m, 1H), 2.38 (s, 3H), 2.28-2.16 (m,2H), 2.22 (s, 3H), 1.71-1.62 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). ChiralHPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=8.07 min, 94.9%, 89.8% de@ 254 nm.

Example 17:(S)-1-(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E1 (70 mg, 0.156mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-chlorophenyl)boronic acid (28 mg, 0.179 mmol)before stirring for 18 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (4 gcolumn, 0-50% MeAc/CH2Cl2) to afford(S)-1-(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (43 mg, 47%) as an off white solid; Rt 1.96 min (method1), m/z 554 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.81-7.72 (m, 1H), 7.64(dd, J=1.7, 0.6 Hz, 1H), 7.61-7.51 (m, 2H), 7.42-7.31 (m, 2H), 7.25 (dd,J=8.5, 1.7 Hz, 1H), 6.08 (dd, J=8.1, 2.3 Hz, 1H), 5.57-5.47 (m, 1H),3.79 (t, J=9.8 Hz, 1H), 3.72 (td, J=9.3, 8.1, 2.8 Hz, 1H), 3.66 (dd,J=10.6, 6.7 Hz, 1H), 3.44-3.35 (m, 1H), 3.10 (s, 3H), 2.78-2.52 (m, 4H),2.49-2.43 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.20-2.14 (m, 1H). ChiralHPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): 148476, RT=9.53 min, 94.8%,89.6% de @ 254 nm.

Example 18:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and pyridin-3-ylboronic acid (15.24 mg, 0.124 mmol)before stirring for 18 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (12 gcolumn, 0-80% MeAc/CH2Cl2) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2-one(23 mg, 39%) as an off white solid; Rt 1.40 min (method 1), m/z 521(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.69 (1H, d, J=2.6 Hz), 8.28 (1H, dd,J=4.7, 1.4 Hz), 7.98 (1H, ddd, J=8.4, 2.6, 1.4 Hz), 7.76 (1H, d, J=8.4Hz), 7.64 (1H, d, J=1.8 Hz), 7.36 (1H, ddd, J=8.4, 4.7, 0.7 Hz), 7.25(1H, dd, J=8.5, 1.7 Hz), 6.13 (1H, d, J=6.4 Hz), 5.58-5.41 (1H, m),3.86-3.75 (1H, m), 3.75-3.59 (2H, m), 3.45-3.35 (1H, m), 3.09 (3H, s),2.76-2.61 (2H, m), 2.61-2.51 (2H, m), 2.36 (3H, s), 2.23 (1H, d, J=8.2Hz), 2.20 (3H, s), 1.14 (1H, s). Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=11.85 min, >99% de @ 254 nm.

Example 19:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2-one

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (6-fluoropyridin-3-yl)boronic acid (17.47 mg,0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2-one(18 mg, 0.033 mmol, 29.3% yield) as an off white solid; Rt 1.70 min(method 1), m/z 539 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.33 (1H, dd,J=3.0, 1.3 Hz), 8.18 (1H, ddd, J=8.9, 7.2, 2.8 Hz), 7.76 (1H, d, J=8.4Hz), 7.64 (1H, d, J=1.6 Hz), 7.25 (1H, dd, J=8.4, 1.7 Hz), 7.18 (1H, dd,J=9.0, 3.3 Hz), 6.15-6.04 (1H, m), 5.51-5.39 (1H, m), 3.85-3.76 (1H, m),3.76-3.61 (2H, m), 3.42-3.34 (1H, m), 3.08 (3H, s), 2.79-2.62 (2H, m),2.51 (3H, s), 2.37 (3H, s), 2.26-2.21 (1H, m), 2.20 (3H, s); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=9.00 min, >99% de @ 254nm.

Example 20:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and naphthalen-1-ylboronic acid (21.33 mg, 0.124mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(12 g column, 0-50% MeAc/CH2Cl2) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one(7 mg, 11%) as an off white solid; Rt 1.86 min (method 1), m/z 570(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.96 (2H, br. s), 7.90 (1H, d, J=8.4Hz), 7.74 (1H, s), 7.64-7.35 (5H, m), 7.18 (1H, d, J=8.4 Hz), 5.99-5.82(1H, m), 4.93 (1H, br. s), 3.68-3.56 (1H, m), 3.45-3.36 (2H, m),3.05-2.81 (6H, m), 2.78-2.63 (2H, m), 2.56-2.51 (2H, m), 2.40 (3H, s),2.23 (3H, s); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=9.23min, 97% de @ 254 nm.

Example 22:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (5-fluoropyridin-3-yl)boronic acid (17.47 mg,0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford a solid. The solidwas dissolved in EtOAc (˜3 mL) and then Hexane (20 mL) was added. Theresultant solid precipitate was collected by filtration, washing withHexane (5 mL), and dried in vacuo to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2-one(12 mg, 20%) as an off white solid; Rt 1.68 min (method 1), m/z 539(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.51 (1H, s), 8.32 (1H, d, J=2.6 Hz),8.14 (1H, dt, J=11.4, 2.3 Hz), 7.78 (1H, d, J=8.5 Hz), 7.64 (1H, d,J=1.6 Hz), 7.26 (1H, dd, J=8.5, 1.7 Hz), 6.24-6.17 (1H, m), 5.55-5.43(1H, m), 3.88-3.78 (1H, m), 3.77-3.64 (2H, m), 3.39 (1H, q, J=8.7 Hz),3.09 (3H, s), 2.76-2.65 (2H, m), 2.65-2.53 (3H, m), 2.36 (3H, s),2.26-2.20 (1H, m), 2.19 (3H, s). Chiral HPLC (Lab 1 Bay 4, DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=9.22 min, >99% de @ 254 nm.

Example 23(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,5-difluorophenyl)boronic acid (19.58 mg,0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford a solid. The solidwas dissolved in EtOAc (˜3 mL) and then Hexane (20 mL) was added. Theresultant solid precipitate was collected by filtration, washing withHexane (5 ml), and dried in vacuo to afford(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(18 mg, 28%) as an off white solid; Rt 1.92 min (method 1), m/z 556(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.7Hz, 1H), 7.41-7.32 (m, 2H), 7.27 (dd, J=8.4, 1.7 Hz, 1H), 7.05-6.93 (m,1H), 6.16 (d, J=7.4 Hz, 1H), 5.60-5.45 (m, 1H), 3.83 (t, J=9.8 Hz, 1H),3.79-3.64 (m, 2H), 3.40 (q, J=9.0 Hz, 1H), 3.10 (s, 3H), 2.78-2.53 (m,5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.16 (d, J=10.1 Hz, 1H); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=10.83 min, >99% de @ 254nm.

Example 24(S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid(23.24 mg, 0.124 mmol) before stirring for 18 h at 40° C. The mixturewas concentrated under reduced pressure then purified by chromatographyon the Companion (12 g column, 0-50% MeAc/CH2Cl2) to afford a solid. Thesolid was dissolved in EtOAc (˜3 ml) and then Hexane (20 ml) was added.The resultant solid precipitate was collected by filtration, washingwith Hexane (5 ml), and dried in vacuo to afford(S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(15 mg, 22%) as a yellow solid; Rt 1.91 min (method 1), m/z 585 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.31 (1H, d, J=2.4 Hz), 8.11 (1H, d, J=2.4Hz), 7.76 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=1.6 Hz), 7.26 (1H, dd,J=8.4, 1.7 Hz), 6.13-6.03 (1H, m), 5.53-5.39 (1H, m), 3.86 (3H, s),3.85-3.78 (1H, m), 3.77-3.61 (2H, m), 3.44-3.36 (1H, m), 3.09 (3H, s),2.78-2.61 (2H, m), 2.59-2.53 (1H, m), 2.48-2.42 (2H, m), 2.38 (3H, s),2.27-2.23 (1H, m), 2.21 (3H, s); Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=8.32 min, >99% de @ 254 nm.

Example 25(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-fluoro-5-methoxyphenyl)boronic acid (21.07mg, 0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one(19 mg, 29%) as an off white solid; Rt 1.91 min (method 1), m/z 568(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 7.12 (dt, J=11.5, 2.1 Hz, 1H),6.95-6.89 (m, 1H), 6.60 (dt, J=10.8, 2.3 Hz, 1H), 6.12 (d, J=8.3 Hz,1H), 5.63-5.49 (m, 1H), 3.87-3.69 (m, 3H), 3.68 (s, 3H), 3.44-3.35 (m,1H), 3.10 (s, 3H), 2.81-2.65 (m, 1H), 2.66-2.52 (m, 4H), 2.38 (s, 3H),2.21 (s, 3H), 2.16 (d, J=9.9 Hz, 1H); Chiral HPLC (Diacel Chiralpak IA,5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=8.56 min, >99% de @ 254 nm.

Example 26:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and 3-(trifluoromethoxy)phenyl)boronic acid (25.5mg, 0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one (20 mg, 29%) as an off white solid; Rt2.09 min (method 1), m/z 604 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.90-7.85(m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.43 (t, J=8.3Hz, 1H), 7.32-7.22 (m, 2H), 7.13-7.06 (m, 1H), 6.13 (d, J=7.5 Hz, 1H),5.59-5.48 (m, 1H), 3.85-3.77 (m, 1H), 3.77-3.61 (m, 2H), 3.44-3.35 (m,2H), 3.09 (s, 3H), 2.79-2.63 (m, 2H), 2.63-2.52 (m, 2H), 2.37 (s, 3H),2.20 (s, 3H), 2.20-2.16 (m, 1H); Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=6.30 min, >99% de @ 254 nm.

Example 27:(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (50 mg, 0.113mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (20.33mg, 0.124 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(24 mg, 37%) as an off white solid; Rt 1.72 min (method 1), m/z 562(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.72 (d, J=8.5 Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.38 (dd, J=2.3, 1.2 Hz, 1H), 7.24 (dd, J=8.5, 1.6 Hz, 1H),7.05 (dd, J=8.5, 2.3 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 5.93 (dd, J=8.3,2.8 Hz, 1H), 5.52-5.40 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.80-3.71 (m,1H), 3.71-3.64 (m, 1H), 3.63-3.55 (m, 1H), 3.33-3.29 (m, 1H), 3.14-3.09(m, 2H), 3.08 (s, 3H), 2.84-2.70 (m, 1H), 2.68-2.57 (m, 1H), 2.49-2.41(m, 2H), 2.39 (s, 3H), 2.26 (s, 1H), 2.22 (s, 3H), 2.21-2.09 (m, 1H);Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=11.67 min, >99%de @ 254 nm.

Example 28:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-dichlorophenyl)boronic acid (25 mg, 0.131mmol) before stirring for 18 h at 40° C. The mixture was diluted withwater then extracted with dichloromethane (3×8 mL). The organic phaseswere combined then filtered and concentrated under reduced pressure. Thecrude product was purified by chromatography on the Companion (4 gcolumn, 2-5% MeOH/DCM) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(48 mg, 62%) as a pale yellow glass; Rt 2.13 min (method 1), m/z 588(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.03 (d, J=2.6 Hz, 1H), 7.80-7.74 (m,1H), 7.68-7.62 (m, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.43 (dd, J=8.9, 2.6 Hz,1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.19-6.12 (m, 1H), 5.61-5.47 (m, 1H),3.87-3.64 (m, 3H), 3.45-3.35 (m, 1H), 3.10 (s, 3H), 2.78-2.53 (m, 5H),2.37 (s, 3H), 2.21 (s, 3H), 2.19-2.12 (m, 1H); Chiral HPLC (DiacelChiralpak IA, 5 um, 4.6×250 mm, 30 min method, 1.0 ml/min, isocratic 30%EtOH in isohexane (0.2% TFA), RT=8.80 min, >99%, >98% de @ 254 nm.

Example 29:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (6-methoxypyridin-3-yl)boronic acid (25 mg,0.163 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2-one(38 mg, 52%) as a pale yellow glass; Rt 1.69 min (method 1), m/z 551(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.19-8.13 (m, 1H), 7.92 (dd, J=8.9,2.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.26 (dd,J=8.5, 1.7 Hz, 1H), 6.81 (dd, J=8.9, 0.6 Hz, 1H), 6.05-5.95 (m, 1H),5.52-5.39 (m, 1H), 3.84-3.78 (m, 1H), 3.77 (s, 3H), 3.74-3.59 (m, 2H),3.40-3.35 (m, 1H), 3.09 (s, 3H), 2.77-2.61 (m, 2H), 2.58-2.52 (m, 1H),2.49-2.43 (m, 1H), 2.38 (s, 3H), 2.37-2.29 (m, 1H), 2.26-2.22 (m, 1H),2.22 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=11.55min, >99%, >98% de @ 254 nm.

Example 30:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol), Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4,5-trifluorophenyl)boronic acid (25 mg,0.142 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one(47 mg, 61%) as a pale yellow glass; Rt 2.05 min (method 1), m/z 574(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.82-7.74 (m, 1H), 7.67-7.63 (m, 1H),7.59 (dd, J=10.5, 6.4 Hz, 2H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 6.13 (d,J=7.3 Hz, 1H), 5.55-5.43 (m, 1H), 3.83 (s, 1H), 3.79-3.64 (m, 2H),3.45-3.35 (m, 1H), 3.10 (s, 3H), 2.77-2.53 (m, 5H), 2.37 (s, 3H), 2.21(s, 3H), 2.19-2.12 (m, 1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): 148497, RT=6.32 min, 98.5%, 97% de @ 254 nm.

Example 31:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (28 mg,0.147 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one(42 mg, 54%) as a pale yellow glass; Rt 2.09 min (method 1), m/z 588(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.83-7.73 (m, 3H), 7.73-7.65 (m, 2H),7.63 (d, J=1.6 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.21-6.12 (m, 1H),5.63-5.48 (m, 1H), 3.88-3.78 (m, 1H), 3.78-3.64 (m, 2H), 3.46-3.36 (m,1H), 3.10 (s, 3H), 2.79-2.54 (m, 5H), 2.37 (s, 3H), 2.25-2.14 (m, 1H),2.20 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=7.19min, >99%, >98% de @ 254 nm.

Example 32:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid (30 mg,0.146 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethoxy)phenyl)pyrrolidin-2-one(40 mg, 50%) as a pale yellow glass; Rt 2.14 min (method 1), m/z 604(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.69-7.59 (m,3H), 7.39-7.29 (m, 2H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.13-6.02 (m, 1H),5.57-5.44 (m, 1H), 3.87-3.76 (m, 1H), 3.76-3.63 (m, 2H), 3.44-3.35 (m,1H), 3.10 (s, 3H), 2.80-2.53 (m, 4H), 2.49-2.40 (m, 1H), 2.38 (s, 3H),2.27-2.15 (m, 1H), 2.21 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=6.26 min, >99%, >98% de @ 254 nm.

Example 33:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-ethoxy-5-fluorophenyl)boronic acid (25 mg,0.136 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one(39 mg, 51%) as a pale yellow glass; Rt 2.02 min (method 1), m/z 582(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 7.08 (dt, J=11.4, 2.1 Hz, 1H),6.94 (t, J=1.8 Hz, 1H), 6.57 (dt, J=10.9, 2.3 Hz, 1H), 6.17-6.07 (m,1H), 5.61-5.49 (m, 1H), 3.94 (dq, J=6.9, 2.2 Hz, 2H), 3.80 (t, J=9.8 Hz,1H), 3.77-3.70 (m, 1H), 3.67 (dd, J=10.6, 6.9 Hz, 1H), 3.43-3.35 (m,1H), 3.10 (s, 3H), 2.81-2.45 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H),2.19-2.13 (m, 1H), 1.25 (t, J=7.0 Hz, 3H); Chiral HPLC (Diacel ChiralpakIA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=8.70 min, >99%, >98% de @ 254 nm.

Example 34:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(o-tolyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(o-tolyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and o-tolylboronic acid (20 mg, 0.147 mmol) beforestirring for 18 h at 40° C. The mixture was diluted with water thenextracted with dichloromethane (3×8 mL). The organic phases werecombined then filtered and concentrated under reduced pressure. Thecrude product was purified by chromatography on the Companion (4 gcolumn, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(o-tolyl)pyrrolidin-2-one(22 mg, 30%) as a pale yellow glass; Rt 1.78 min (method 1), m/z 534(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.73 (d, J=1.6 Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.30-7.06 (m, 5H), 5.84-5.69 (m, 1H), 5.21-5.06 (m, 1H),3.75-3.66 (m, 1H), 3.58-3.44 (m, 2H), 3.19-3.09 (m, 1H), 3.03 (s, 3H),2.94-2.82 (m, 1H), 2.78-2.65 (m, 1H), 2.64-2.52 (m, 3H), 2.42 (s, 3H),2.25 (s, 3H), 2.17-2.00 (m, 1H), 2.05 (s, 3H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=6.68 min, >96.8%, >93.6% de @ 254 nm.

Example 35:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (5-fluoro-2-methylphenyl)boronic acid (22 mg,0.143 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one(16 mg, 21%) as a pale yellow glass; Rt 1.84 min (method 1), m/z 552(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.72 (d, J=1.6 Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.31-7.21 (m, 2H), 7.21-7.12 (m, 1H), 7.06 (td, J=8.5, 2.8 Hz,1H), 5.84-5.75 (m, 1H), 5.34-5.21 (m, 1H), 3.73 (dd, J=10.6, 8.8 Hz,1H), 3.60 (td, J=9.2, 2.6 Hz, 1H), 3.53 (dd, J=10.6, 6.8 Hz, 1H),3.28-3.17 (m, 1H), 3.05 (s, 3H), 2.90-2.65 (m, 2H), 2.61-2.52 (m, 1H),2.49-2.45 (m, 1H), 2.41 (s, 3H), 2.27-2.15 (m, 1H), 2.24 (s, 3H), 2.07(s, 3H). Chiral HPLC (Lab 1 Bay 4, Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=6.53 min, >99%, >98% de @ 254 nm.

Example 36:3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-cyano-5-fluorophenyl)boronic acid (25 mg,0.152 mmol) before stirring for 18 h at 40° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile(35 mg, 47%) as a pale yellow glass; Rt 1.92 min (method 1), m/z 563(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.94-7.86 (m, 2H), 7.78 (d, J=8.5 Hz,1H), 7.64 (d, J=1.6 Hz, 1H), 7.60 (ddd, 1H), 7.27 (dd, J=8.5, 1.7 Hz,1H), 6.22 (d, J=7.1 Hz, 1H), 5.56-5.43 (m, 1H), 3.89-3.80 (m, 1H),3.80-3.73 (m, 1H), 3.69 (dd, J=10.6, 6.8 Hz, 1H), 3.46-3.36 (m, 1H),3.10 (s, 3H), 2.78-2.53 (m, 5H), 2.37 (s, 3H), 2.28-2.12 (m, 1H), 2.20(s, 3H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=8.95min, >99%, >98% de @ 254 nm.

Example 37:(S)-1-(cyclohex-1-en-1-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile

A solution of DBU (50 μl, 0.332 mmol) and Intermediate E1 (150 mg, 0.321mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and cyclohex-1-en-1-ylboronic acid (50 mg, 0.397mmol) before stirring for 18 h at 70° C. The mixture was diluted withwater then extracted with dichloromethane (3×8 mL). The organic phaseswere combined then filtered and concentrated under reduced pressure. Thecrude product was purified by chromatography on the Companion (4 gcolumn, 2-5% MeOH/DCM) to afford(S)-1-(cyclohex-1-en-1-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(58 mg, 0.105 mmol, 32.7% yield) as a pale yellow glass; Rt 1.78 min(method 1), m/z 524 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78 (d, J=8.5 Hz,1H), 7.71 (d, J=1.6 Hz, 1H), 7.27 (dd, J=8.4, 1.6 Hz, 1H), 5.58 (dd,J=8.2, 2.6 Hz, 1H), 5.55-5.44 (m, 1H), 5.43-5.36 (m, 1H), 3.82-3.62 (m,3H), 3.44-3.34 (m, 2H), 2.70-2.52 (m, 2H), 2.50-2.42 (m, 3H), 2.41 (s,3H), 2.40-2.03 (m, 5H), 2.25 (s, 3H), 1.98-1.89 (m, 2H), 1.56-1.35 (m,4H). Contains 1.9% w/w isohexane; Chiral HPLC (Diacel Chiralpak IA, 5μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=7.95 min, 97.5%, 95% de @ 254 nm.

Example 38:(S)-1-(4,5-difluoro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile

A solution of DBU (20 μL, 0.133 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4,5-difluoro-2-methylphenyl)boronic acid (25mg, 0.145 mmol) before stirring for 18 h at 70° C. The mixture wasdiluted with water then extracted with dichloromethane (3×8 mL). Theorganic phases were combined then filtered and concentrated underreduced pressure. The crude product was purified by chromatography onthe Companion (4 g column, 2-5% MeOH/DCM) to afford a pale brown gum.The gum was purified by chromatography on the Companion (RP Flash C18)(12 g column, 15-75% MeCN/Water 0.1% Formic Acid) to afford(S)-1-(4,5-difluoro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(22 mg, 28%) as a pale yellow glass; Rt 1.99 min (method 1), m/z 570(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.75-7.67 (m, 2H), 7.47 (dd, J=11.5,7.9 Hz, 1H), 7.34 (dd, J=11.7, 8.9 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz,1H), 5.77 (dd, J=7.9, 3.5 Hz, 1H), 5.37-5.26 (m, 1H), 3.79-3.69 (m, 1H),3.68-3.59 (m, 1H), 3.55 (dd, J=10.6, 6.7 Hz, 1H), 3.33-3.21 (m, 2H),3.06 (s, 3H), 2.86-2.64 (m, 2H), 2.59-2.53 (m, 1H), 2.46-2.42 (m, 1H),2.41 (s, 3H), 2.35-2.24 (m, 1H), 2.24 (s, 3H), 2.11 (s, 3H).

The product was analysed by Chiral HPLC (Lab 1 Bay 4, Diacel ChiralpakIA, 5 um, 4.6×250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH inisohexane (0.2% TFA): 1561183, RT=6.17 min, >99%, >98% de @ 254 nm.

Example 39:(S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (21 μL, 0.139 mmol) and Intermediate E1 (60 mg, 0.129mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-dichloro-2-methylphenyl)boronic acid (30mg, 0.146 mmol) before stirring for 18 h at 70° C. The mixture wasdiluted with water then extracted with dichloromethane (3×8 mL). Theorganic phases were combined then filtered and concentrated underreduced pressure. The crude product was purified by chromatography onthe Companion (4 g column, 2-5% MeOH/DCM) to afford a pale brown gum.The gum was purified by chromatography on the Companion (RP Flash C18)(12 g column, 15-75% MeCN/Water 0.1% Formic Acid) to afford(S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (14 mg, 17%)as a pale yellow glass; Rt 2.10 min (method 1), m/z 602 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.77-7.60 (m, 2H), 7.58-7.45 (m, 1H), 7.47-7.01 (m,2H), 6.06-5.54 (m, 1H), 5.40-5.20 (m, 1H), 3.81-3.68 (m, 1H), 3.67-3.58(m, 1H), 3.58-3.47 (m, 1H), 3.32-3.20 (m, 2H), 3.06 (s, 3H), 2.89-2.69(m, 2H), 2.65-2.54 (m, 1H), 2.47-2.37 (m, 1H), 2.41 (s, 3H), 2.35-2.12(m, 4H), 2.24 (s, 3H).

Example 40:(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-fluorophenyl)boronic acid (25 mg, 0.179 mmol)before stirring for 18 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (12 gcolumn, 0-50% MeAc/DCM) to afford(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one (41 mg, 48%) as an off white solid; Rt 1.85 min (method1), m/z 538 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.76 (1H, d, J=8.5 Hz),7.69-7.57 (2H, m), 7.39-7.18 (3H, m), 6.92 (1H, tdd, J=8.4, 2.6, 0.9Hz), 6.10 (1H, d, J=6.9 Hz), 5.59-5.42 (1H, m), 3.85 (1H, dd, J=10.5,8.9 Hz), 3.78-3.62 (2H, m), 3.49-3.37 (1H, m), 3.11 (3H, s), 2.79-2.60(2H, m), 2.60-2.52 (2H, m), 2.49-2.43 (1H, m), 2.37 (3H, s), 2.20 (3H,s), 2.17-2.08 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=10.83 min, >99% de @ 254 nm.

Example 41:(R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and boronic acid (3,4-difluorophenyl)boronic acid(27.4 mg, 0.174 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(31 mg, 35%) as an off white solid; Rt 1.91 min (method 1), m/z 556(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.85 (1H, ddd, J=13.3, 7.4, 2.7 Hz),7.76 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=1.6 Hz), 7.41-7.31 (1H, m),7.28-7.19 (2H, m), 6.11-6.04 (1H, m), 5.54-5.40 (1H, m), 3.83 (1H, dd,J=10.5, 8.8 Hz), 3.77-3.64 (2H, m), 3.48-3.36 (1H, m), 3.10 (3H, s),2.75-2.60 (2H, m), 2.60-2.51 (3H, m), 2.37 (3H, s), 2.20 (3H, s),2.14-2.09 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=9.57 min, >99% de @ 254 nm.

Example 42:(R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-chloro-3-fluorophenyl)boronic acid (30.3 mg,0.174 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-50% MeAc/DCM) to afford(R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(30 mg, 33%) as an off white solid; Rt 2.03 min (method 1), m/z 572(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.86 (1H, dd, J=12.2, 2.5 Hz), 7.77(1H, d, J=8.5 Hz), 7.63 (1H, d, J=1.5 Hz), 7.50 (1H, t, J=8.8 Hz), 7.30(1H, ddd, J=9.0, 2.6, 1.0 Hz), 7.26 (1H, dd, J=8.5, 1.7 Hz), 6.11 (1H,d, J=6.7 Hz), 5.55-5.41 (1H, m), 3.89 (1H, dd, J=10.5, 8.8 Hz), 3.73(2H, dd, J=10.4, 7.1 Hz), 3.49-3.35 (1H, m), 3.11 (3H, s), 2.76-2.61(2H, m), 2.61-2.51 (3H, m), 2.36 (3H, s), 2.20 (3H, s), 2.14-2.08 (1H,m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method,1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=11.66min, >99% de @ 254 nm.

Example 43:(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,5-dichlorophenyl)boronic acid (33.1 mg, 0.174mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(12 g column, 0-40% MeAc/DCM) to afford(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (40 mg, 43%) as an off white solid; Rt 2.15 min (method1), m/z 588 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (1H, d, J=8.5 Hz),7.70 (2H, d, J=1.8 Hz), 7.65 (1H, d, J=1.7 Hz), 7.34 (1H, t, J=1.8 Hz),7.26 (1H, dd, J=8.4, 1.7 Hz), 6.21 (1H, d, J=7.0 Hz), 5.55-5.43 (1H, m),3.92-3.84 (1H, m), 3.78-3.66 (2H, m), 3.49-3.39 (1H, m), 3.12 (3H, s),2.75-2.62 (2H, m), 2.61-2.52 (3H, m), 2.37 (3H, s), 2.20 (3H, s), 2.11(1H, s); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=9.00min, >99% de @ 254 nm.

Example 44:(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-4-fluorophenyl)boronic acid (30.3 mg,0.174 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-40% MeAc/DCM) to afford(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[i]imidazol-2-yl)pyrrolidin-2-one(27 mg, 30%) as an off white solid; Rt 1.97 min (method 1), m/z 572(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.02-7.96 (1H, m), 7.76 (1H, d, J=8.4Hz), 7.65 (1H, d, J=1.6 Hz), 7.42-7.31 (2H, m), 7.25 (1H, dd, J=8.5, 1.7Hz), 6.13-6.07 (1H, m), 5.53-5.42 (1H, m), 3.82 (1H, dd, J=10.5, 8.8Hz), 3.77-3.64 (2H, m), 3.48-3.36 (1H, m), 3.10 (3H, s), 2.77-2.60 (2H,m), 2.61-2.51 (3H, m), 2.37 (3H, s), 2.20 (3H, s), 2.15-2.10 (1H, m);Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=10.55 min, >99%de @ 254 nm.

Example 45:(R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and Intermediate E23 (70 mg, 0.158mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,5-dichlorophenyl)boronic acid (33.1 mg, 0.174mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(12 g column, 0-40% MeAc/DCM) to afford(R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(31 mg, 34%) as an off white solid; Rt 2.05 min (method 1), m/z 572(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78 (1H, d, J=8.4 Hz), 7.68-7.59 (2H,m), 7.46 (1H, dt, J=11.4, 2.1 Hz), 7.26 (1H, dd, J=8.5, 1.7 Hz), 7.16(1H, dt, J=8.5, 2.1 Hz), 6.16 (1H, d, J=6.9 Hz), 5.54-5.41 (1H, m), 3.90(1H, dd, J=10.4, 8.8 Hz), 3.78-3.67 (2H, m), 3.50-3.38 (1H, m), 3.12(3H, s), 2.78-2.61 (2H, m), 2.61-2.51 (3H, m), 2.37 (3H, s), 2.20 (3H,s), 2.15-2.09 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=8.76 min, >99% de @ 254 nm.

Example 46:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide(Intermediate D3)

HATU (550 mg, 1.446 mmol) was added to a solution of Intermediate C3(194 mg, 0.526 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (200 mg,1.549 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.546 mmol) inN,N-dimethylformamide (5 mL) then stirred at room temperature for 18 h.The mixture was diluted with 30% brine (100 mL) then extracted withethyl acetate (3×75 mL). The combined organic phases were dried (MgSO4),filtered and concentrated under reduced pressure to yield a red-brownoil. The oil was dissolved in acetone (25 mL) then diluted with diethylether (75 mL). The resulting precipitate was collected by filtration toyield(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D3 (438 mg, 68%) as a pale brown solid; Rt 1.36 min (method1), m/z 447 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one(Intermediate E3)

Intermediate D3 (438 mg, 0.961 mmol) was heated to 80° C. in acetic acid(10 mL) for 4 h. The volatiles were removed under reduced pressure thenthe residue was diluted with saturated sodium hydrogen carbonatesolution (25 mL) and extracted with dichloromethane (3×20 mL). Thecombined organic phases were dried (Na2SO4) then filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on the Companion (24 g column, 50-100% MeAc/CH2Cl2) toafford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E3 (139 mg, 33%) as a colourless glass; Rt 1.32 min (method1), m/z 429 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-difluorophenyl)boronic acid (25 mg, 0.158mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(31 mg, 39%) as an off white solid; Rt 1.88 min (method 1), m/z 541(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.85 (ddd, J=13.3, 7.4, 2.7 Hz, 1H),7.69-7.59 (m, 2H), 7.37 (dt, J=10.7, 9.2 Hz, 1H), 7.29 (dd, J=8.5, 1.7Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 5.99 (d, J=7.3 Hz, 1H), 5.02 (t, J=12.3Hz, 1H), 3.58 (q, J=12.7 Hz, 2H), 3.32-3.23 (m, 2H), 2.90 (q, J=13.1 Hz,2H), 2.78-2.51 (m, 3H), 2.38 (s, 3H), 2.35-2.22 (m, 2H), 2.21 (s, 3H),2.19-2.10 (m, 1H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):148480, RT=8.82 min, 96.9%, 93.8% de @ 254 nm.

Example 47:(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-4-fluorophenyl)boronic acid (25 mg,0.143 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(34 mg, 42%) as an off white solid; Rt 1.94 min (method 1), m/z 557(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.98 (dt, J=6.9, 1.4 Hz, 1H),7.70-7.58 (m, 2H), 7.39-7.33 (m, 2H), 7.29 (dd, J=8.5, 1.7 Hz, 1H), 6.01(d, J=7.1 Hz, 1H), 5.11-4.95 (m, 1H), 3.68-3.48 (m, 2H), 3.32-3.23 (m,2H), 2.90 (q, J=13.0 Hz, 2H), 2.80-2.52 (m, 3H), 2.38 (s, 3H), 2.32-2.11(m, 3H), 2.21 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=8.90 min, 96.1%, 92.2% de @ 254 nm.

Example 48:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-fluorophenyl)boronic acid (20 mg, 0.143 mmol)before stirring for 18 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (4 gcolumn, 0-50% MeAc/DCM) to afford a colourless gum. The gum wasdissolved in methyl ethyl ketone (0.5 mL) then diluted with diethylether (2 mL). The supernatant was removed then the solid was driedovernight in a desiccator at 50° C. to give(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one (23 mg, 30%) as whitesolid; Rt 1.80 min (method 1), m/z 523 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ:7.70-7.56 (m, 3H), 7.39-7.24 (m, 2H), 7.24-7.14 (m, 1H), 6.93 (tdd,J=8.4, 2.5, 0.9 Hz, 1H), 6.01 (d, J=7.4 Hz, 1H), 5.12-4.98 (m, 1H), 3.58(t, J=13.6 Hz, 2H), 3.33-3.25 (m, 2H), 2.91 (q, J=12.9 Hz, 2H),2.80-2.62 (m, 2H), 2.60-2.52 (m, 1H), 2.38 (s, 3H), 2.34-2.10 (m, 3H),2.21 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): 148483,RT=11.76 min, >99%, >98% de @ 254 nm.

Example 49:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (4-chloro-3-fluorophenyl)boronic acid (25 mg,0.143 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/CH2Cl2) to afford a gum. The gumwas triturated in diethyl ether to yield(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(41 mg, 50%) as an off white solid; Rt 2.00 min (method 1), m/z 557(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.87 (dd, J=12.1, 2.5 Hz, 1H),7.71-7.57 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.30 (dd, J=8.5, 1.6 Hz, 1H),7.25 (ddd, J=8.9, 2.6, 1.0 Hz, 1H), 6.03 (d, J=7.2 Hz, 1H), 5.13-4.93(m, 1H), 3.58 (dd, J=16.1, 7.0 Hz, 2H), 3.33-3.23 (m, 2H), 2.92 (q,J=12.9 Hz, 2H), 2.79-2.62 (m, 2H), 2.62-2.52 (m, 1H), 2.40-2.26 (m, 2H),2.37 (s, 3H), 2.20 (s, 3H), 2.18-2.10 (m, 1H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=10.81 min, 98.3%, 96.6% de @ 254 nm.

Example 50:(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-5-methoxyphenyl)boronic acid (28 mg,0.150 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford a colourless gum.The gum was dissolved in methyl ethyl ketone (0.5 mL) then diluted withdiethyl ether. The supernatant was removed then the solid was driedovernight in a desiccator at 50° C. to yield(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(47 mg, 57%) as a white solid; Rt 1.94 min (method 1), m/z 569 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.66 (d, J=1.6 Hz, 1H), 7.63 (d, J=8.6 Hz,1H), 7.33 (t, J=1.9 Hz, 1H), 7.30 (dd, J=8.5, 1.7 Hz, 1H), 7.06 (t,J=2.1 Hz, 1H), 6.79 (t, J=2.0 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H), 5.16-4.99(m, 1H), 3.69 (s, 3H), 3.64-3.51 (m, 2H), 3.33-3.26 (m, 2H), 3.02-2.83(m, 2H), 2.83-2.52 (m, 3H), 2.38 (s, 3H), 2.35-2.23 (m, 1H), 2.21 (s,3H), 2.19-2.08 (m, 2H; Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): 148485, RT=10.72 min, >99%, >98% de @ 254 nm.

Example 51:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid (25 mg,0.147 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford a gum. The gum wasdissolved in methyl ethyl ketone (0.5 mL) then diluted with diethylether (2 mL). The supernatant was removed then the solid was driedovernight in a desiccator at 50° C.(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(28 mg, 35%) as an off white solid; Rt 1.76 min (method 1), m/z 553(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.70-7.56 (m, 3H), 7.29 (dd, J=8.4,1.6 Hz, 1H), 7.15-7.02 (m, 2H), 5.93 (d, J=7.7 Hz, 1H), 5.11-4.93 (m,1H), 3.75 (s, 3H), 3.65-3.48 (m, 2H), 3.32-3.23 (m, 2H), 2.88 (d, J=13.4Hz, 2H), 2.81-2.53 (m, 3H), 2.38 (s, 3H), 2.35-1.98 (m, 6H), 2.21 (s,3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method,1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): 148486, RT=12.91min, >99%, >98% de @ 254 nm.

Example 52:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (28 mg,0.150 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford a gum. The gum wasdissolved in methyl ethyl ketone (0.5 mL) then diluted with diethylether (3 mL). The supernatant was removed and the solid was dried at 50°C. in a desiccator overnight to yield(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(39 mg, 48%) as an off white solid; Rt 1.83 min (method 1), m/z 569(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.80 (d, J=2.6 Hz, 1H), 7.66 (d, J=1.6Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.27 (td, J=8.7, 2.1 Hz, 2H), 7.07 (d,J=9.1 Hz, 1H), 5.96 (d, J=7.8 Hz, 1H), 5.11-4.98 (m, 1H), 3.77 (s, 3H),3.64-3.49 (m, 2H), 3.33-3.23 (m, 2H), 2.95-2.52 (m, 5H), 2.38 (s, 3H),2.34-2.14 (m, 2H), 2.20 (s, 3H), 2.05-1.92 (m, 1H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=12.12 min, >99%, >98% de @ 254 nm.

Example 53:(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,5-dichlorophenyl)boronic acid (28 mg, 0.147mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) then triturated in diethyl ether to afford(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(49 mg, 60%) as an off white solid; Rt 2.12 min (method 1), m/z 573(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.70 (d, J=1.9 Hz, 2H), 7.67-7.61 (m,2H), 7.34 (t, J=1.8 Hz, 1H), 7.31 (dd, J=8.4, 1.7 Hz, 1H), 6.13 (d,J=7.6 Hz, 1H), 5.14-4.98 (m, 1H), 3.69-3.50 (m, 2H), 3.33-3.25 (m, 2H),3.04-2.84 (m, 2H), 2.83-2.53 (m, 3H), 2.38 (s, 3H), 2.35-2.22 (m, 2H),2.21 (s, 3H), 2.18-2.11 (m, 1H); Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=10.02 min, >99%, >98% de @ 254 nm.

Example 54:(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3-chloro-5-fluorophenyl)boronic acid (25 mg,0.143 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford a gum which wastriturated in diethyl ether to yield(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(28 mg, 34%) as an off white solid; Rt 2.02 min (method 1), m/z 557(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.67-7.62 (m, 2H), 7.62-7.57 (m, 1H),7.47 (dt, J=11.4, 2.1 Hz, 1H), 7.31 (dd, J=8.5, 1.6 Hz, 1H), 7.17 (dt,J=8.5, 2.1 Hz, 1H), 6.09 (d, J=7.4 Hz, 1H), 5.12-4.96 (m, 1H), 3.71-3.48(m, 2H), 3.29 (d, J=4.0 Hz, 2H), 3.05-2.84 (m, 2H), 2.83-2.53 (m, 3H),2.38 (s, 3H), 2.36-2.23 (m, 2H), 2.21 (s, 3H), 2.18-2.10 (m, 1H); ChiralHPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=10.55 min, >99%, >98% de@ 254 nm.

Example 55:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4,5-trifluorophenyl)boronic acid (25 mg,0.142 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one (49 mg, 61%) as an off white solid; Rt 2.00 min (method1), m/z 559 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.69-7.52 (m, 4H), 7.30(dd, J=8.5, 1.6 Hz, 1H), 6.03 (d, J=6.9 Hz, 1H), 5.06-4.88 (m, 1H), 3.64(td, J=13.6, 3.5 Hz, 1H), 3.55 (td, J=13.7, 3.5 Hz, 1H), 3.33-3.24 (m,2H), 2.92 (q, J=13.1 Hz, 2H), 2.77-2.63 (m, 2H), 2.63-2.53 (m, 1H),2.41-2.27 (m, 2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.17-2.10 (m, 1H); ChiralHPLC (Diacel Chiralpak IA, 5 mm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=9.04 min, >99%, >98% de @254 nm.

Example 56:(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,5-difluorophenyl)boronic acid (23 mg, 0.146mmol) before stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% MeAc/DCM) to afford(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(36 mg, 43%) as an off white solid; Rt 1.92 min (method 1), m/z 541(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.69-7.60 (m, 2H), 7.41-7.33 (m, 2H),7.30 (dd, J=8.6, 1.6 Hz, 1H), 6.98 (tt, J=9.2, 2.3 Hz, 1H), 6.05 (d,J=7.3 Hz, 1H), 5.02 (t, J=12.4 Hz, 1H), 3.70-3.48 (m, 2H), 3.33-3.24 (m,2H), 3.04-2.85 (m, 2H), 2.80-2.53 (m, 3H), 2.38 (s, 3H), 2.36-2.28 (m,2H), 2.21 (s, 3H), 2.13 (q, J=7.9, 7.3 Hz, 1H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=11.07 min, >99%, >98% de @ 254 nm.

Example 57:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (5-fluoro-6-methoxypyridin-3-yl)boronic acid (25mg, 0.146 mmol) before stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (4 g column, 0-50% MeAc/DCM) then triturated in diethylether to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one(20 mg, 26%) as an off white solid; Rt 1.78 min (method 1), m/z 554(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.13 (dd, J=12.2, 2.3 Hz, 1H), 7.97(d, J=2.2 Hz, 1H), 7.71-7.58 (m, 2H), 7.30 (dd, J=8.4, 1.7 Hz, 1H), 5.96(d, J=7.2 Hz, 1H), 5.04-4.88 (m, 1H), 3.86 (s, 3H), 3.70-3.57 (m, 1H),3.57-3.46 (m, 1H), 3.33-3.24 (m, 2H), 3.00-2.79 (m, 2H), 2.79-2.63 (m,2H), 2.60-2.52 (m, 1H), 2.38 (s, 3H), 2.36-2.25 (m, 1H), 2.25-2.15 (m,2H), 2.21 (s, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=12.97 min, >99%, >98% de @ 254 nm.

Example 58:(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (25 mg,0.152 mmol) before stirring for 18 h at 70° C. The mixture was dilutedwith water then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(35 mg, 44%) as a pale yellow glass; Rt 1.68 min (method 1), m/z 547(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.68 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 7.01 (dd,J=8.6, 2.3 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 5.84 (d, J=7.8 Hz, 1H),5.04-4.91 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.61-3.42 (m, 2H), 3.31-3.20(m, 2H), 3.10 (t, J=8.7 Hz, 2H), 2.93-2.72 (m, 3H), 2.71-2.58 (m, 1H),2.44-2.33 (m, 1H), 2.39 (s, 3H), 2.32-2.10 (m, 2H), 2.22 (s, 3H),1.75-1.61 (m, 1H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=16.8 min, 97.4%, 94.8% de @ 254 nm.

Example 59:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E3 (60 mg, 0.139mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-dichlorophenyl)boronic acid (28 mg, 0.147mmol) before stirring for 18 h at 70° C. The mixture was diluted withwater then extracted with dichloromethane (3×8 mL). The organic phaseswere combined then filtered and concentrated under reduced pressure. Thecrude product was purified by chromatography on the Companion (4 gcolumn, 2-5% MeOH/DCM) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(41 mg, 49%) as a pale yellow glass; Rt 2.08 min (method 1), m/z 573(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.07 (d, J=2.5 Hz, 1H), 7.68-7.60 (m,2H), 7.56 (d, J=8.9 Hz, 1H), 7.39 (dd, J=8.9, 2.6 Hz, 1H), 7.30 (dd,J=8.5, 1.6 Hz, 1H), 6.06 (d, J=7.2 Hz, 1H), 5.14-4.97 (m, 1H), 3.66-3.51(m, 2H), 3.33-3.23 (m, 2H), 3.00-2.84 (m, 2H), 2.80-2.52 (m, 3H), 2.37(s, 3H), 2.35-2.25 (m, 2H), 2.21 (s, 3H), 2.18-2.10 (m, 1H); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=10.91 min, 83.6%, 67.2%de @ 254 nm.

Example 61:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(1r,4S)-4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D4)

HATU (1.5 g, 3.94 mmol) was added to a stirred solution of TEA (0.6 ml,4.30 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.5 g, 3.87 mmol)and(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexanol(1.15 g, 3.78 mmol) in N,N-dimethylformamide (10 mL) then the mixturewas stirred at room temperature for 18 h.

The solvents were removed under reduced pressure (co-evaporating withxylenes) then adsorbed onto loose silica gel. The silicate was purifiedby flash chromatography on the Companion (80 g column, 0-10% MeOH/DCM)to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D4 (1.5 g, 89%) as a pale pink solid; Rt 1.31 min (method1), m/z 413 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (Intermediate E4)

Intermediate D4 (500 mg, 1.115 mmol) was heated to 80° C. in acetic acid(10 mL) for 4 h. The mixture was concentrated under reduced pressurethen redissolved in methanol (20 mL). Solid potassium carbonate (2 g)was added and the mixture was stirred for 1 h before concentrating ontoloose silica gel. The crude product was purified by chromatography onthe Companion (40 g column, 5-15% MeOH/DCM) to afford a colourless gum.The gum was stirred overnight in diethyl ether (25 mL) then collected byfiltration to yield(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E4) (232 mg, 52%) as a white solid; Rt 1.13 min (method1), m/z 395 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μL, 0.146 mmol) and Intermediate E4 (55 mg, 0.137mmol) in acetonitrile (4 mL) was added to a vial charged with CuTMEDA(10 mg, 0.022 mmol) and (3,4-difluorophenyl)boronic acid (25 mg, 0.158mmol) before stirring for 2 h at 70° C. The mixture was diluted withwater (8 mL) then extracted with dichloromethane (3×8 mL). The organicphases were combined then filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (4 g column, 2-5% MeOH/DCM) to afford a pale brown gum. Thegum was purified by chromatography on the Companion (12 g column, 0-10%MeOH/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(40 mg, 56%) as an off white solid; Rt 1.78 min; m/z 507 (M+H)+ (ES+);1H NMR (d₆-DMSO) δ: 7.89-7.76 (m, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.44-7.33(m, 1H), 7.22-7.11 (m, 2H), 6.17-6.05 (m, 1H), 4.75 (d, J=4.2 Hz, 1H),4.57-4.43 (m, 1H), 3.82-3.66 (m, 1H), 2.81-2.52 (m, 3H), 2.43-2.26 (m,2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.14-2.05 (m, 1H), 2.04-1.93 (m, 2H),1.87-1.79 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.39 (m, 2H).

Example 62:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol), Intermediate E4 (50 mg, 0.127 mmol) and(4-chloro-3-fluorophenyl)boronic acid (24.31 mg, 0.139 mmol) inacetonitrile (4 ml) with stirring for 108 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-10% MeOH in DCM, gradient elution) toafford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(15 mg, 22%) as an off white solid; Rt 1.56 min; m/z 523 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.87-7.79 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.52 (t,J=8.8 Hz, 1H), 7.23 (ddd, J=8.9, 2.6, 1.0 Hz, 1H), 7.16 (dd, J=8.5, 1.7Hz, 1H), 6.22-6.08 (m, 1H), 4.76 (d, J=4.2 Hz, 1H), 4.59-4.45 (m, 1H),3.81-3.67 (m, 1H), 2.80-2.53 (m, 3H), 2.41-2.29 (m, 2H), 2.36 (s, 3H),2.20 (s, 3H), 2.11-1.95 (m, 3H), 1.89-1.78 (m, 2H), 1.63-1.39 (m, 2H).

Example 63:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μl,0.133 mmol), Intermediate E4 (50 mg, 0.127 mmol) and(3-fluoro-4-methoxyphenyl)boronic acid (23.70 mg, 0.139 mmol) inacetonitrile (4 mL) with stirring for 108 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-10% MeOH in DCM, gradient elution) toafford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(9 mg, 13%) as an off white solid; Rt 1.69 min; m/z 519 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.81 (d, J=8.5 Hz, 1H), 7.59 (td, J=7.2, 6.5, 1.9 Hz,2H), 7.14 (dd, J=8.5, 1.7 Hz, 1H), 7.12-7.03 (m, 2H), 6.04 (dd, J=8.4,2.2 Hz, 1H), 4.75 (d, J=4.1 Hz, 1H), 4.56-4.43 (m, 1H), 3.82-3.65 (m,1H), 3.75 (s, 3H), 2.82-2.52 (m, 3H), 2.37 (s, 3H), 2.35-2.25 (m, 2H),2.20 (s, 3H), 2.15-2.06 (m, 1H), 2.03-1.91 (m, 2H), 1.84-1.75 (m, 1H),1.65-1.39 (m, 3H).

Example 64:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol), Intermediate E4 and (3-chloro-4-methoxyphenyl)boronic acid(26.0 mg, 0.139 mmol) in acetonitrile (4 mL) with stirring for 108 h at40° C. The mixture was concentrated under reduced pressure then purifiedby chromatography on the Companion (12 g column, 0-10% MeOH in DCM,gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(15 mg, 22%) as an off white solid; Rt 1.76 min; m/z 535 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.80 (d, J=8.5 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.59(d, J=1.7 Hz, 1H), 7.27 (dd, J=9.0, 2.6 Hz, 1H), 7.13 (dd, J=8.5, 1.7Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.11-6.03 (m, 1H), 4.74 (d, J=4.2 Hz,1H), 4.50 (s, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 2.83-2.69 (m, 1H),2.67-2.53 (m, 1H), 2.37 (s, 3H), 2.28 (d, J=12.3 Hz, 1H), 2.20 (s, 3H),2.15-2.05 (m, 1H), 1.96 (t, J=13.6 Hz, 3H), 1.77 (m, 1H), 1.52 (m, 3H).

Example 65:(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one]

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol), Intermediate E4 (50 mg, 0.127 mmol) and(3-chloro-4-fluorophenyl)boronic acid (24.31 mg, 0.139 mmol) inacetonitrile (4 mL) with stirring for 108 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-10% MeOH in DCM, gradient elution) toafford(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(16 mg, 24%) as an off white solid; Rt 1.90 min; m/z 523 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.92 (dt, J=6.8, 1.4 Hz, 1H), 7.82 (d, J=8.5 Hz,1H), 7.58 (d, J=1.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.14 (dd, J=8.4, 1.7 Hz,1H), 6.17-6.10 (m, 1H), 4.75 (d, J=4.2 Hz, 1H), 4.50 (s, 1H), 3.72 (m,1H), 2.75 (dt, J=15.4, 9.1 Hz, 1H), 2.66-2.54 (m, 1H), 2.36-2.31 (m,6H), 2.19 (s, 3H), 2.14-2.03 (m, 1H), 1.97 (s, 2H), 1.82 (s, 1H), 1.71(s, 1H), 1.50 (dd, J=29.4, 13.8 Hz, 2H).

Example 66:(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol),(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.127 mmol) and(2,3-dihydrobenzofuran-5-yl)boronic acid (22.86 mg, 0.139 mmol) inacetonitrile (4 mL) with stirring for 108 h at 40° C. The mixture wasconcentrated under reduced pressure then purified by chromatography onthe Companion (12 g column, 0-10% MeOH in DCM, gradient elution) toafford(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(13 mg, 19%) as an off white solid; Rt 1.59 min; m/z 513 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.38(dd, J=2.2, 1.2 Hz, 1H), 7.12 (dd, J=8.4, 1.7 Hz, 1H), 7.01 (dd, J=8.6,2.3 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 5.94 (dd, J=8.3, 2.7 Hz, 1H), 4.72(d, J=4.2 Hz, 1H), 4.45 (m, 4H), 3.67 (m, 1H), 3.43-3.28 (m, 1H),3.20-3.05 (m, 2H), 2.78 (dt, J=16.0, 9.0 Hz, 1H), 2.66-2.51 (m, 1H),2.38 (s, 3H), 2.31-2.15 (m, 5H), 2.01-1.91 (m, 1H), 1.88 (m, 1H), 1.75(m, 1H), 1.48-1.30 (m, 3H).

Example 67:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μl,0.133 mmol), Intermediate E4 (50 mg, 0.127 mmol) andnaphthalen-1-ylboronic acid (23.98 mg, 0.139 mmol) in acetonitrile (4ml) with stirring for 108 h at 40° C. The mixture was concentrated underreduced pressure then purified by chromatography on the Companion (12 gcolumn, 0-10% MeOH in DCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one(4 mg, 6%) as an off white solid; Rt 1.75 min; m/z 521 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.96 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.68 (s, 1H),7.60 (d, J=8.6 Hz, 1H), 7.40 (bs, 6H), 7.07 (d, J=8.4 Hz, 1H), 5.89 (s,1H), 4.54 (s, 1H), 3.81 (bs, 1H), 3.38 (bm, 2H), 2.96 (bs, 1H), 2.84(bs, 1H), 2.73 (bm, 4H), 2.40 (s, 3H), 2.22 (s, 3H), 1.99 (bm, 1H), 1.75(m, 2H), 1.63 (m, 1H)—Broad spectrum, rotamers.

Example 68:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μl,0.133 mmol), Intermediate E4 (50 mg, 0.127 mmol) and(3,4-dichlorophenyl)boronic acid (26.6 mg, 0.139 mmol) in acetonitrile(4 ml) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(25 mg, 36%) as an off white solid; Rt 2.03 min; m/z 539 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H),7.63-7.50 (m, 2H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.16 (dd, J=8.5, 1.7Hz, 1H), 6.24-6.13 (m, 1H), 4.76 (d, J=4.3 Hz, 1H), 4.60-4.46 (m, 1H),3.84-3.63 (m, 1H), 2.82-2.53 (m, 3H), 2.42-2.28 (m, 2H), 2.37 (s, 3H),2.20 (s, 3H), 2.13-1.93 (m, 3H), 1.89-1.74 (m, 2H), 1.65-1.39 (m, 2H);Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): 156120, RT=5.88 min,98%, 96% ee @ 254 nm

Example 69:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D5)

A solution of Intermediate C5 (500 mg, 1.556 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (651 mg, 1.711 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (221 mg, 1.711 mmol) andtriethylamine (651 μl, 4.67 mmol) in DMF (5 mL) was stirred at roomtemperature for 18 h. The mixture was partitioned between DCM (20 mL)and saturated sodium bicarbonate (10 mL). The organic phase wascollected and washed sequentially with saturated sodium bicarbonate (10mL) and water (2×10 mL), then the layers separated through a PhaseSep©cartridge. The organic phase was evaporated in vacuo and to the crudeIntermediate D5 (quantitative yield assumed) was used without furtherpurification; Rt 1.38 min; m/z 433 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E5)

A solution of Intermediate D5 (336 mg, 0.777 mmol) in acetic acid (1 ml)was heated to 80° C. for 18 h. The solvent was removed in vacuo and theresidue was purified by chromatography (12 g silica, 0-10% methanol inDCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E5 (80 mg, 24%) as a glassy white solid;

Example 70:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (13.11 mg, 0.028 mmol) was added to a solution of DBU (29.8 μL,0.198 mmol), Intermediate E5 (78 mg, 0.188 mmol) and(3,4-difluorophenyl)boronic acid (32.7 mg, 0.207 mmol) in acetonitrile(4 mL) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by flash chromatography on theCompanion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(12 mg, 12%) as an off white solid; Rt 1.96 min; m/z 527 (M+H)+ (ES+);

Example 71: Tert-butyl(S)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylateTert-butyl(8)-3-((2-((8)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamido)-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidin-1-carboxylate(Intermediate D6)

A solution of Intermediate C6 (600 mg, 1.611 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (674 mg, 1.772 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (229 mg, 1.772 mmol) andtriethylamine (674 μL, 4.83 mmol) in DMF (5 mL) was stirred at roomtemperature for 18 h. The mixture was partitioned between DCM (20 mL)and saturated sodium bicarbonate (10 mL). The organic phase wascollected and washed sequentially with saturated sodium bicarbonate (10mL) and water (2×10 mL), then the layers separated through a PhaseSep©cartridge. The organic phase was evaporated in vacuo and to the looseresidue was added DCM (2 mL). 1 mL of the solution was removed viapipette and used (after removing the solvent) in 1493-51. The remainingsolution was concentrated in vacuo into the crude Intermediate D6(quantitative yield assumed), which was used without furtherpurification; Rt 1.93 min; m/z 384 (M+H)+ (ES+).

(S)-tert-butyl3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(Intermediate E6)

A solution of Intermediate D6 (389 mg, 0.804 mmol) in acetic acid (1mlL) was heated to 80° C. for 18 h. The solvent was removed in vacuo andthe residue was purified by chromatography (12 g silica, 0-10% methanolin DCM, gradient elution) to afford (S)-tert-butyl3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate Intermediate E6 (54 mg, 14%) as a glass whichscratched to a white solid; Rt 1.77 min; m/z 466 (M+H)+ (ES.

Tert-butyl(S)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate

CuTMEDA (7.78 mg, 0.017 mmol) was added to a solution of DBU (17.68 μL,0.117 mmol), Intermediate E6 (52 mg, 0.112 mmol) and(3,4-difluorophenyl)boronic acid (19.40 mg, 0.123 mmol) in acetonitrile(4 ml) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by flash chromatography on theCompanion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-tert-butyl3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(28 mg, 43%) as an off white solid; Rt 2.36 min; m/z 578 (M+H)+ (ES+);7.82 (s, 1H), 7.71-7.60 (m, 2H), 7.43-7.31 (m, 1H), 7.27-7.15 (m, 2H),6.08 (s, 1H), 5.40 (m, 1H), 3.87 (m, 1H), 3.75-3.65 (m, 2H), 3.39 (m,1H), 2.67-2.53 (m, 2H), 2.36 (s, 3H), 2.33 (m, 1H), 2.19 (s, 3H), 2.13(m, 1H), 1.45 (d, J=9.6 Hz, 9H). 2H's short

Example 72: Tert-butyl(R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(R)-tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate

A mixture of Intermediate A (10 g, 42.3 mmol) and (R)-tert-butyl3-aminopyrrolidine-1-carboxylate (7.89 g, 42.3 mmol) was stirred in dryTHF (100 mL) and TEA (17.70 mL, 127 mmol) was added. The reaction wasstirred at rt for 18 h, then heated to 40° C. and stirred for 72 h, thenheated to 50° C. and stirred for 18 h. After cooling to RT, the reactionmixture was poured into ice water (300 mL). The mixture was extractedwith ethyl acetate (2×500 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to afford(R)-tert-butyl-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(17.85 g, 96%) as a thick orange oil; Rt 2.48 min; m/z 403 (M+H)+ (ES+).

(R)-tert-butyl3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate

(R)-tert-butyl3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate(17.04 g, 42.3 mmol) was dissolved in THF/water (1:1, 1,000 mL).Concentrated ammonia (33.0 mL, 847 mmol) and sodium dithionite (73.7 g,423 mmol) were added and the reaction stirred at RT for 18 h. EtOAc (500mL) was added, the mixture transferred to a separating funnel and washedsequentially with 1M NaOH (400 mL) and brine (200 mL). The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo to give a lightfluffy solid. The material was triturated with diethyl ether andcollected by filtration. The filtrate was concentrated in vacuo toafford a light fluffy peach solid. After LCMS and NMR analysis thetriturated material and the material obtained from the filtrate werecombined to afford (R)-tert-butyl3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate(13.58 g, 85%) as a light peach fluffy solid; Rt 2.24 min; m/z 372(M+H)+ (ES+).

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

A solution of (R)-tert-butyl3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate(600 mg, 1.611 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (674 mg, 1.772 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (229 mg, 1.772 mmol) andtriethylamine (674 μL, 4.83 mmol) in DMF (5 mL) was stirred at roomtemperature for 18 h. The mixture was partitioned between DCM (20 mL)and saturated sodium bicarbonate (10 mL). The organic phase wascollected and washed sequentially with saturated sodium bicarbonate (10mL) and water (2×10 mL), then the layers separated through a PhaseSep©cartridge. The organic phase was evaporated in vacuo to afford the crude(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (quantitative yieldassumed), which was used without further purification; Rt 1.94 min; m/z384 (M+H)+ (ES+).

(R)-tert-butyl3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate

A solution of(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(342 mg, 0.829 mmol) in acetic acid was heated to 80° C. for 3 h. Thesolvent was removed in vacuo and the residue was purified bychromatography (12 g silica, 0-10% methanol in DCM, gradient elution) toafford (R)-tert-butyl3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(54 mg, 14%) as a glass which scratched to a white solid; Rt 1.77 min;m/z 466 (M+H)+ (ES+).

Tert-butyl(R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[i]imidazol-1-yl)pyrrolidine-1-carboxylate

CuTMEDA (7.78 mg, 0.017 mmol) was added to a solution of DBU (17.68 μL,0.117 mmol), (R)-tert-butyl3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (52 mg, 0.112 mmol) and(3,4-difluorophenyl)boronic acid (19.40 mg, 0.123 mmol) in acetonitrile(4 mL) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(R)-tert-butyl3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(28 mg, 43% yield) as an off white solid; Rt 2.38 min; m/z 578 (M+H)+(ES+); 7.82 (ddd, J=13.1, 7.3, 2.7 Hz, 1H), 7.71-7.60 (m, 2H), 7.38 (dt,J=10.6, 9.2 Hz, 1H), 7.19 (dd, J=8.4, 1.8 Hz, 1H), 6.07 (d, J=8.1 Hz,1H), 5.46-5.37 (m, 1H), 3.72 (m, 3H), 3.42 (m, 1H), 2.79-2.53 (m, 2H),2.36 (s, 3H), 2.32 (m, 1H), 2.19 (s, 3H), 2.15 (d, J=10.5 Hz, 1H), 1.44(d, J=13.6 Hz, 9H).

Example 73:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of (S)-tert-butyl3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(26 mg, 0.045 mmol) in DCM (5 ml) and TFA (1 ml) was stirred at rt for 1h. The solvents were removed in vacuo to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(22 mg, 0.046 mmol, 102% yield) as a smear on the inside of thescintillation vial; Rt 1.31 min; m/z 478 (M+H)+ (ES+);

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(21 mg, 0.044 mmol) and methanesulfonyl chloride (3.74 μL, 0.048 mmol)in DCM (2 mL) was added DIPEA (15.36 μL, 0.088 mmol). The reactionmixture was stirred at RT for 18 h, then DIPEA (38.4 μL, 0.220 mmol) andmethanesulfonyl chloride (6.81 μL, 0.088 mmol) were added. Afterstirring for 1 h, the reaction was diluted with DCM (10 mL) and washedwith 0.2M aqueous hydrochloric acid (5 mL). The organic phase wascollected via PhaseSep© cartridge and concentrated in vacuo. The residuewas purified by chromatography (4 g silica, 0-10% methanol in DCM,gradient elution). Product fractions were concentrated in vacuo and theresidue triturated with ether to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (13 mg, 53%)as a white solid; Rt 1.96 min; m/z 556 (M+H)+ (ES+); 1H NMR (400 MHz,DMSO-d6) δ 7.90-7.73 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.44-7.30 (m, 1H),7.24 (ddd, J=11.3, 8.1, 1.5 Hz, 2H), 6.11-6.04 (m, 1H), 5.47 (p, J=8.6Hz, 1H), 3.83 (dd, J=10.5, 8.8 Hz, 1H), 3.70 (dd, J=10.4, 7.0 Hz, 2H),3.47-3.28 (m, 2H), 3.10 (d, J=6.1 Hz, 3H), 2.75-2.51 (m, 2H), 2.46 (m,2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.11 (m, 1H).

Example 74: (S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of (R)-tert-butyl3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate(29 mg, 0.050 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at RT for 1h. The solvents were removed in vacuo to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(24 mg, 100% yield) as a smear on the inside of the scintillation vial;Rt 1.35 min; m/z 478 (M+H)+ (ES+).

(S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

To a solution of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(24 mg, 0.050 mmol) and cyclopropanesulfonyl chloride (5.63 μl, 0.055mmol) in DCM (2 mL) was added DIPEA (17.56 μl, 0.101 mmol). The reactionmixture was stirred at RT for 18 h. The reaction mixture was stirred atRT for 18 h, then DIPEA (43.9 μl, 0.251 mmol) and cyclopropanesulfonylchloride (10.24 μl, 0.101 mmol) were added. After stirring for 1 h, thereaction was diluted with DCM (10 mL) and washed with 0.2M aqHCl (5 mL).The organic phase was collected via phase sep cartridge and concentratedin vacuo. The residue was purified by chromatography (4 g silica, 0-10%methanol in DCM, gradient elution). Product fractions were concentratedin vacuo and the residue triturated with ether to afford(S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(8 mg, 27%) as a white solid; Rt 2.10 min; m/z 582 (M+H)+ (ES+); 1H NMR(400 MHz, DMSO-d6) δ 7.82 (ddd, J=13.2, 7.4, 2.7 Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.44-7.30 (m, 1H), 7.30-7.17 (m, 2H),6.07 (dd, J=10.5, 8.1 Hz, 1H), 5.52 (t, J=8.0 Hz, 1H), 3.93-3.65 (m,3H), 3.46 (q, J=8.8 Hz, 1H), 2.96-2.83 (m, 1H), 2.77-2.44 (m, 4H), 2.37(s, 3H), 2.20 (m, 4H), 2.20-2.06 (m, 1H), 1.09 (s, 1H), 1.10-0.97 (m,3H).

Example 75:(S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

Acetyl chloride (8.11 μL, 0.114 mmol) was added to a solution of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(66 mg, 0.104 mmol) and DIPEA (0.036 ml, 0.207 mmol) in DCM (3 ml). Thereaction was stirred for 16 hours, water (3 ml) was added and the phasesseparated. The organic layer was dried (MgSO4), filtered andconcentrated in vacuo. The crude product was purified by chromatographyon the Companion (40 g column, 0-10% MeOH/DCM) and further purified bypreparative HPLC (Waters, Acidic (0.1% Formic acid) Waters X-SelectPrep-C18, 5 μm, 19×50 mm column, 15-35% MeCN in Water) to afford(S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(10 mg, 18%) as a light white solid; Rt 1.80 min (method 1), m/z 520(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.73-7.55 (m, 3H), 7.36-7.14 (m, 3H),6.02-5.94 (m, 1H), 5.48-5.38 (m, 1H), 3.90 (m, 3H), 3.56 (m, 1H),2.86-2.63 (m, 2H), 2.61-2.50 (m, 1H), 2.37 (s, 3H), 2.23-2.17 (1H, m)2.19 (s, 3H), 2.04 (s, 3H).

Example 76:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DIPEA (0.057 mL, 0.328 mmol) was added to a solution of3,3,3-trifluoropropanoic acid (0.016 ml, 0.180 mmol), HATU (81 mg, 0.213mmol) and(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(89 mg, 0.164 mmol) in DMF (2 ml, 25.8 mmol) stirred at RT for 3 h. Thereaction mixture was diluted with EtOAc (10 ml) and washed with water (5ml). The organic layer was separated and then dried over MgSO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography on the Companion (40 g column, 0-10% MeOH/DCM) andfurther purified by preparative HPLC (Varian, Acidic (0.1% Formic acid),Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-50% MeCN inWater) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5 mg, 5%) as white solid; Rt 2.09 min (method 1), m/z 588 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.75-7.55 (m, 3H), 7.35-7.15 (m, 3H), 5.98 (d, J=7.8Hz, 1H), 5.45 (m, 1H), 3.96 (m, 3H), 3.54 (m, 3H), 2.85-2.5 (m, 6H),2.36 (s, 3H), 2.19 (s, 3H).

Example 77:(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

HATU (1.111 g, 2.92 mmol) was added to a solution of4-(3,5-dimethylisoxazol-4-yl)-N1-(1-methylpyrrolidin-3-yl)benzene-1,2-diamine(0.82 g, 2.86 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.373 g,2.89 mmol) and DIPEA (0.545 ml, 3.12 mmol) in N,N-dimethylformamide (5mL) then stirred at room temperature for 18 h. The mixture was dilutedwith 30% brine solution (100 mL) then extracted with ethyl acetate (3×75mL). The aqueous layer was concentrated in vacuo to give a yellow solid.The solid was sonicated in DCM (100 mL)/MeOH (100 mL). The suspensionwas filtered and the liquor was concentrated in vacuo to give a yellowsticky oil (2.7 g), which was supported on silica. The crude waspurified by chromatography column (12 g, DCM/10% NH3/MeOH in DCM: 100/0to 0/100 to give(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (0.68 g, 59%) was isolated as a sticky gum; Rt0.81 min (method 1), m/z 398 (M+H)+ (ES+).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(0.68 g, 1.711 mmol) was dissolved in acetic acid (6.86 mL, 120 mmol)and stirred at 70° C. for 15 h. The reaction was cooled down to RT. andconcentrated in vacuo to give a brown oil. The oil was dissolved in DCM(20 mL) and washed with aqueous sodium bicarbonate solution (20 mL). Theaqueous layer was extracted with DCM (20 mL). The organic extracts werecombined and concentrated in vacuo to give a brown oil (0.73 g), whichwas purified by flash chromatography (4 g, 0-10% MeOH in DCM) to give(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(0.38 g, 53%) as a beige foam; Rt 0.83 min (method 1), m/z 380 (M+H)+(ES+).

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL,0.138 mmol),(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one Intermediate E7 (50 mg, 0.132 mmol) and(3,4-difluorophenyl)boronic acid (22.89 mg, 0.145 mmol) in acetonitrile(3.99 mL, 76 mmol) with stirring for 15 h at 40° C. The reaction mixturewas cooled down to RT, then concentrated under reduced pressure andpurified by flash chromatography on the Companion (12 g column, 0-10%MeOH in DCM, gradient elution) to afford(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(20.8 mg, 31%) as an off white foam; Rt 1.25 min (method 1), m/z 492(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.13 (d, 1H), 7.86-7.72 (m, 1H), 7.59(s, 1H), 7.44-7.31 (m, 1H), 7.25-7.16 (m, 2H), 6.16-6.07 (m, 1H),5.43-5.30 (m, 1H), 3.21-3.05 (m, 2H), 2.81-2.53 (m, 4H), 2.47-2.26 (s+m,8H), 2.20 (s, 3H), 2.17-2.01 (m, 2H).

Example 78:(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL,0.138 mmol),(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.132 mmol) and (4-chloro-3-fluorophenyl)boronic acid (25.3 mg,0.145 mmol) in acetonitrile (3.99 mL, 76 mmol) with stirring for 15 h at40° C. The reaction mixture was cooled down to RT and concentrated underreduced pressure then purified by chromatography on the Companion (12 gcolumn, 0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(33.8 mg, 49%) as an offwhite foam; Rt 1.36 min (method 1), m/z 508(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.13 (dd, J=25.6, 8.5 Hz, 1H), 7.81(ddd, J=12.4, 10.1, 2.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.56-7.46 (m, 1H),7.32-7.25 (m, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 6.19-6.11 (m, 1H),5.43-5.33 (m, 1H), 3.24-3.06 (m, 2H), 2.80-2.52 (m, 4H), 2.45-2.28 (m,7H), 2.19 (s, 3H), 2.16-2.01 (m, 2H).

Example 79:(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL,0.138 mmol),(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.132 mmol) and (3,4-dichlorophenyl)boronic acid (27.7 mg, 0.145mmol) in acetonitrile (3.99 mL, 76 mmol) with stirring for 15 h at 40°C. The reaction mixture was cooled down to RT, concentrated underreduced pressure then purified by flash chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(31 mg, 43%) as a yellowish solid; Rt 1.42 min (method 1), m/z 524(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.13 (dd, J=16.9, 8.4 Hz, 1H), 8.00(dd, J=2.6 Hz, 1H), 7.60-7.53 (d+dd, 2H), 7.43 (ddd, J=18.4, 8.9, 2.6Hz, 1H), 7.21 (dd, J=8.5, 1.7 Hz, 1H), 6.21-6.16 (m, 1H), 5.43-5.36 (m,1H), 3.24-3.07 (m, 2H), 2.79-2.52 (m, 4H), 2.45-2.27 (m, 8H), 2.20 (s,3H), 2.17-2.01 (m, 2H).

Example 80:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D8)

A solution of Intermediate C8 (680 mg, 2.156 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouroniumhexafluorophosphate(V) (902 mg, 2.372 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (306 mg, 2.372 mmol) andtriethylamine (901 μL, 6.47 mmol) in DMF (20 mL) was stirred at roomtemperature for 3 h. The mixture was partitioned between ethyl acetate(200 mL) and water (100 mL), then the layers separated. The organicphase was washed with water (100 mL), passed through a PhaseSep©cartridge and evaporated in vacuo to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide Intermediate D8 (0.96 g, quantitative yield)as a crude residue, which was used without further purification; Rt 1.65min (method 1), m/z 427 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E8)

A solution of Intermediate D8 (0.92 g, 2.157 mmol) in acetic acid (1 mL)was heated to 80° C. for 18 h. The solvent was removed in vacuo and theresidue was purified by chromatography (12 g silica, 0-10% methanol inDCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one Intermediate E8 (480 mg, 52%) as a glass whichscratched to an orange solid; Rt 1.41 min (method 1), m/z 409 (M+H)+(ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol)) was added to a solution of DBU (19.37 μL,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(3,4-difluorophenyl)boronic acid (21.26 mg, 0.135 mmol) in acetonitrile(4 ml) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure. The residue was taken up in the minimum of DCM,passed through a syringe filter and the solution purified bychromatography on the Companion (4 g column, 0-10% MeOH in DCM, gradientelution) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(33 mg, 51%) as an off white solid; Rt 2.16 min (method 1), m/z 521(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77 (d, J=8.7 Hz, 1H), 7.67 (m, 1H),7.54 (s, 1H), 7.29 (d, J=9.7 Hz, 1H), 7.15 (m, 2H), 5.98 (s, 1H), 4.51(s, 1H), 3.45 (s, 1H), 2.92 (s, 4H), 2.37 (s, 5H), 2.20 (s, 7H), 1.79(s, 2H), 1.48 (m, 3H).

Example 81:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(3,4-dichlorophenyl)boronic acid (25.7 mg, 0.135 mmol) in acetonitrile(4 ml) with stirring for 18 h at 40° C. The mixture was concentratedunder reduced pressure. The residue was taken up in the minimum of DCM,passed through a syringe filter and the solution purified bychromatography on the Companion (12 g column, 0-10% MeOH in DCM,gradient elution) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(35 mg, 51%) as an off white solid; Rt 2.39 min (method 1), m/z 553(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 7.61-7.53 (m, 2H), 7.41 (dd, J=8.9, 2.5 Hz, 1H), 7.15 (dd,J=8.5, 1.7 Hz, 1H), 6.20-6.13 (m, 1H), 4.58 (t, J=12.7 Hz, 1H), 3.44 (m,1H), 3.31 (s, 4H), 2.75 (dt, J=15.4, 9.0 Hz, 1H), 2.66-2.51 (m, 1H),2.36 (m, 5H), 2.19 (m, 4H), 2.07 (t, J=10.5 Hz, 1H), 1.94-1.81 (m, 3H),1.45 (dt, J=37.1, 12.1 Hz, 2H).

Example 82:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (25.10 mg, 0.135 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(49 mg, 0.088 mmol, 72.2% yield) as an off white solid; Rt 2.11 min(method 1), m/z 549 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.82 (d, J=8.5 Hz,1H), 7.75 (d, J=2.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.27 (dd, J=9.0,2.6 Hz, 1H), 7.18-7.03 (m, 2H), 6.06 (dd, J=8.2, 2.3 Hz, 1H), 4.55 (t,J=11.9 Hz, 1H), 3.76 (s, 3H), 3.44 (m, 1H), 3.30 (s, 3H), 2.77 (dt,J=16.0, 9.1 Hz, 1H), 2.67-2.52 (m, 1H), 2.45 (m, 1H), 2.37 (s, 3H), 2.29(m, 2H), 2.20 (s, 3H), 2.12 (m, 3H), 1.85 (d, J=12.3 Hz, 1H), 1.62 (d,J=12.1 Hz, 1H), 1.44 (dd, J=21.1, 11.4 Hz, 2H).

Example 83:(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(2,3-dihydrobenzofuran-5-yl)boronic acid (22.08 mg, 0.135 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(46 mg, 71%) as an off white solid; Rt 1.88 min (method 1), m/z 527(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.8Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.13 (dd, J=8.5, 1.7 Hz, 1H), 7.01 (dd,J=8.5, 2.4 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 5.97-5.89 (m, 1H), 4.45 (m,2H), 3.29 (d, J=8.7 Hz, 1H), 3.29 (s, 3H), 3.20-3.04 (m, 2H), 2.77 (dd,J=16.3, 8.9 Hz, 1H), 2.60 (m, 1H), 2.38 (s, 3H), 2.28 (m, 1H), 2.21 (s,3H), 2.16 (m, 1H), 2.12 (m, 4H), 1.81 (d, J=12.4 Hz, 1H), 1.38 (m, 4H).

Example 84:(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(3-chloro-4-fluorophenyl)boronic acid (23.48 mg, 0.135 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (34 mg, 51%) as an off white solid; Rt2.24 min (method 1), m/z 537 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.91 (dt,J=6.8, 1.2 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H),7.40-7.33 (m, 2H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 6.13 (d, J=7.1 Hz, 1H),4.56 (t, J=12.2 Hz, 1H), 3.41 (m, 1H), 3.31 (s, 3H), 2.76 (dt, J=15.7,9.0 Hz, 1H), 2.67-2.51 (m, 1H), 2.36-2.29 (m, 5H), 2.20-2.16 (m, 6H),2.09 (t, J=10.8 Hz, 1H), 1.88 (d, J=12.7 Hz, 1H), 1.75 (d, J=12.2 Hz,1H), 1.45 (dq, J=24.3, 10.9 Hz, 2H).

Example 85:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(4-chloro-3-fluorophenyl)boronic acid (23.48 mg, 0.135 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(36 mg, 54%) as an off white solid; Rt 2.28 min (method 1), m/z 537(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.89-7.79 (m, 2H), 7.58 (d, J=1.6 Hz,1H), 7.52 (t, J=8.8 Hz, 1H), 7.22 (ddd, J=9.0, 2.5, 1.0 Hz, 1H), 7.15(dd, J=8.5, 1.7 Hz, 1H), 6.14 (d, J=7.1 Hz, 1H), 4.62-4.51 (m, 1H),3.52-3.42 (m, 1H), 3.31 (s, 3H), 2.80-2.50 (m, 3H), 2.36 (m, 5H), 2.19(m, 5H), 2.06 (t, J=10.4 Hz, 1H), 1.89 (s, 2H), 1.46 (dq, J=35.4, 11.8Hz, 2H).

Example 86:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μl,0.129 mmol), Intermediate E8 (50 mg, 0.122 mmol) and(3-fluoro-4-methoxyphenyl)boronic acid (22.88 mg, 0.135 mmol) inacetonitrile (4 mL) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(16 mg, 24%) as an off white solid; Rt 2.01 min (method 1), m/z 533(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.82 (d, J=8.5 Hz, 1H), 7.64-7.55 (m,2H), 7.18-7.02 (m, 3H), 6.04 (d, J=7.2 Hz, 1H), 4.54 (s, 1H), 3.74 (s,3H), 3.50-3.35 (m, 1H), 3.30 (s, 3H), 2.74 (dd, J=15.9, 9.3 Hz, 1H),2.67-2.52 (m, 1H), 2.37 (s, 3H), 2.34-2.23 (m, 1H), 2.20 (m, 4H),2.14-2.08 (m, 4H), 1.87 (s, 1H), 1.64 (d, J=11.5 Hz, 1H), 1.43 (t,J=13.3 Hz, 2H).

Example 87:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(1R,4s)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate

DIAD (110 μL, 0.566 mmol) was added to a solution of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(150 mg, 0.290 mmol), acetic acid (50 μL, 0.873 mmol) andtriphenylphosphine (200 mg, 0.763 mmol) in tetrahydrofuran (2 mL) thenstirred at room temperature for 1 h. DIAD (110 μL, 0.566 mmol) was addedand the mixture was stirred for a further 18 h. The mixture wasconcentrated onto loose silica gel then the silicate was purified bychromatography on the Companion (12 g column, 5-25% THF/CH2Cl2) toafford(1R,4s)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate (109 mg, 66%) as a white solid; Rt 2.20 min (method 1), m/z 549(M+H)+ (ES+);

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

Potassium carbonate (50 mg, 0.362 mmol) was added to a solution of(1R,4s)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate (108 mg, 0.191 mmol) in methanol (3 mL) and tetrahydrofuran (3mL) then stirred at room temperature for 1 h. Methanol (8 mL) was addedfollowed by 1.0 M aqueous hydrogen chloride (1.0 ml, 1.000 mmol). Thesolution was loaded onto SCX (1 g) the washed with methanol (3×10 mL).The product was eluted with 0.7 M ammonia in methanol (3×5 ml) to yield(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (97mg, 0.182 mmol, 95% yield) as a white solid; Rt 1.81 min (method 1), m/z507 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.6 Hz,1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.39 (dd, J=10.7,9.2 Hz, 1H), 7.23 (dd, J=8.5, 1.7 Hz, 1H), 7.20-7.13 (m, 1H), 6.10 (dd,J=8.1, 1.9 Hz, 1H), 4.73 (d, J=2.9 Hz, 1H), 4.64-4.49 (m, 1H), 4.05-3.91(m, 1H), 2.81-2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.14-2.04 (m,1H), 1.93-1.81 (m, 2H), 1.79-1.50 (m, 4H).

Example 88:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

Sodium hydride, 60% dispersion in mineral oil (5 mg, 0.125 mmol) wasadded to a solution of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(51 mg, 0.096 mmol) in N,N-dimethylformamide (2 mL) then stirred for 2minutes at room temperature. Iodomethane (7 μL, 0.112 mmol) was addedthen the mixture was stirred at room temperature overnight. Ammoniumchloride (15 mg, 0.280 mmol) was added then the mixture was purified bychromatography on the Companion (RP Flash C18) (12 g column, 15-75%MeCN/Water 0.1% Formic Acid) then by chromatography on the Companion (4g column, 5-15% THF/DCM) then triturated in diethyl ether to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(6 mg, 11%) as a white solid; Rt 2.22 min (method 1), m/z 521 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.6 Hz, 1H), 7.61 (d,J=1.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.39 (dd, J=10.6, 9.2 Hz, 1H),7.24 (dd, J=8.4, 1.7 Hz, 1H), 7.20-7.14 (m, 1H), 6.10 (d, J=7.6 Hz, 1H),4.68-4.52 (m, 1H), 3.60-3.52 (m, 1H), 3.36 (s, 3H), 2.82-2.52 (m, 4H),2.49-2.40 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 2.16-2.03 (m, 3H),1.75-1.52 (m, 4H).

Example 89:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,4s)-4-ethoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-ethoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

NaHMDS (148 μL, 0.148 mmol) was added to a suspension of(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(75 mg, 0.148 mmol) in dry THF (849 μL, 10.36 mmol) at 0° C. Thesuspension was stirred for 5 mn. DMF (894 μl, 11.55 mmol) was added todissolve the solid. Then ethyl iodide (14.36 μL, 0.178 mmol) was addeddropwise. After 4.5 h of stirring, the reaction was diluted into DCM (5mL) and was with saturated aqueous ammonium chloride (10 mL). The layerswere separated and the organic layer was washed with water (5 mL). Theorganic was combined and concentrated in vacuo to give a brown oil,which was purified by chromatography column (4 g, DCM/MeOH: 100/0 to90/10) then (4 g, DCM/MeOH: 100/0 to 90/10) to give(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(10.6 mg, 13%) as a white solid; Rt 2.25 min (method 1), m/z 535 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.88-7.77 (m, 2H), 7.59 (d, J=1.7 Hz, 1H),7.44-7.32 (m, 1H), 7.19-7.11 (m, 2H), 6.10 (dd, 1H), 4.59-4.47 (m, 1H),3.61-3.47 (m+q, 3H), 2.81-2.50 (m, 3H), 2.41-2.26 (m+s, 5H), 2.19 (s,3H), 2.16-2.03 (m, 3H), 1.91-1.83 (m, 1H), 1.81-1.73 (m, 1H), 1.54-1.39(m, 2H), 1.14 (t, J=7.0 Hz, 3H).

Example 90:(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D9)

A solution of Intermediate C9 (1.8 g, 5.37 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (2.245 g, 5.90 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (0.762 g, 5.90 mmol) andtriethylamine (2.24 mL, 16.10 mmol) in DMF (20 mL) was stirred at roomtemperature for 3 h. The mixture was partitioned between ethyl acetate(200 mL) and water (100 mL), then the layers separated. The organicphase was washed with water (100 mL), passed through a PhaseSep© andevaporated in vacuo to afford(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D9 (1.05 g, 35%) as a crude residue; Rt 1.42 min (method1), m/z 447 (M+H)+ (ES+).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E9)

A solution of(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(1.05 g, 2.352 mmol) in acetic acid (5 mL) was heated to 80° C. for 48 hthen left to cool to RT. The reaction was cooled down to RT andconcentrated in vacuo to give a brown oil, which was dissolved in MeOHthen loaded onto a SCX column. The column was washed with MeOH and thenthe product was eluted with 7 M ammonia in MeOH (30 ml). The resultantmixture was concentrated in vacuo then sonicated with diethyl ether (15mL) and concentrated again to afford a brown solid (520 mg).Purification by flash chromatography (4 g, DCM/AcOEt: 100/0 to 60/40then DCM/10% MeOH in DCM: 60/40 to 0/100) to afford(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(0.295 g, 27%) as an off white solid; Rt 1.33 min (method 1), m/z 429(M+H)+ (ES+).

(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL,0.123 mmol),(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.117 mmol) and (3,4-dichlorophenyl)boronic acid (24.49 mg,0.128 mmol) in acetonitrile (3.535 mL, 67.7 mmol) with stirring for 15 hat 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(30.6 mg, 43%) as a yellow solid; Rt 2.10 min (method 1), m/z 573 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.17-8.12 (m, 1H), 8.12-8.04 (m, 1H), 7.62(dd, J=9.2, 1.6 Hz, 1H), 7.54 (dd, J=8.9, 6.1 Hz, 1H), 7.46 (d, J=9.3Hz, 0.5H), 7.33 (dd, 0.5H), 7.21 (ddd, J=8.4, 6.5, 1.7 Hz, 1H),6.39-6.24 (m, 0.5H), 6.02-5.90 (m, 0.5H), 4.99-4.89 (m, 0.5H), 4.88-4.75(m, 0.5H), 4.23-4.08 (m, 1H), 3.81-3.61 (m, 1H), 3.61-3.49 (m, 1H),3.27-3.14 (m, 1H), 2.80-2.55 (m, 2H), 2.54-2.42 (m, 3H), 2.36 (d, J=3.7Hz, 3H), 2.27-2.06 (m+d, 5H), 2.07-1.92 (m, 1H).

Example 91:(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL,0.123 mmol), Intermediate E9 (50 mg, 0.117 mmol) and(4-chloro-3-fluorophenyl)boronic acid (22.38 mg, 0.128 mmol) inacetonitrile (3.535 mL, 67.7 mmol) with stirring for 15 h at 40° C.After 15 h of stirring, the mixture was concentrated under reducedpressure. The residue was taken up in the minimum of DCM, passed througha syringe filter and the solution then purified by chromatography on theCompanion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (34mg, 50%) as a yellow solid; Rt 2.03 min (method 1), m/z 557 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.19-8.08 (m, 1H), 7.87 (ddd, J=12.9, 10.5,2.5 Hz, 1H), 7.61 (dd, J=9.8, 1.7 Hz, 1H), 7.53-7.43 (m, 1H), 7.38-7.24(m, 1H), 7.24-7.18 (m, 1H), 6.33-6.26 (m, 0.5H), 5.99-5.86 (m, 0.5H),4.99-4.87 (m, 0.5H), 4.86-4.75 (m, 0.5H), 4.21-4.07 (m, 1H), 3.86-3.63(m, 1H), 3.61-3.48 (m, 1H), 3.26-3.15 (m, 1H), 2.77-2.65 (m, 1H),2.65-2.54 (m, 1H), 2.50 (m, J=1.8 Hz, 2H), 2.36 (d, J=4.1 Hz, 3H),2.27-2.01 (m+d, 6H), 1.99 (m, 1H).

Example 92:(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL,0.123 mmol),(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.117 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (23.93mg, 0.128 mmol) in acetonitrile (3.53 mL, 67.7 mmol) with stirring for15 h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(27 mg, 39%) as a yellow solid; Rt 1.84 min (method 1), m/z 569 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.16-8.03 (m, 1H), 7.80 (dd, J=39.1, 2.6 Hz,1H), 7.64 (dd, J=9.8, 1.6 Hz, 1H), 7.33 (d, 0.5H), 7.25-7.15 (m, 1.5H),7.06 (dd, J=9.1, 1.7 Hz, 1H), 6.19-6.12 (m, 0.5H), 5.94-5.87 (m, 0.5H),4.96-4.79 (m, 1H), 4.17-4.07 (m, 1H), 3.77 (s, 3H), 3.68-3.43 (m, 2H),3.24-3.13 (m, 1H), 2.80-2.52 (m, 2H), 2.51-2.38 (m, 2H)-2.37 (d, J=3.8Hz, 3H), 2.35-2.24 (m, 1H), 2.20 (d, 3H), 2.20-2.00 (m, 2H), 1.97-1.70(m, 1H).

Example 93:(5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL,0.123 mmol), Intermediate E9 (50 mg, 0.117 mmol) and(2,3-dihydrobenzofuran-5-yl)boronic acid (21.05 mg, 0.128 mmol) inacetonitrile (3.53 mL, 67.7 mmol) with stirring for 15 h at 40° C. Themixture was concentrated under reduced pressure. The residue was takenup in the minimum of DCM, passed through a syringe filter and thesolution then purified by chromatography on the Companion (12 g column,0-10% MeOH in DCM, gradient elution) to afford(5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(28 mg, 42%) as a yellow solid; Rt 1.72 min (method 1), m/z 547 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.13-8.02 (m, 1H), 7.65 (dd, J=8.2, 1.7 Hz,1H), 7.38 (dd, J=44.0, 2.2 Hz, 1H), 7.21-7.16 (m, 1H), 7.06 (dd, J=8.6,2.3 Hz, 0.5H), 6.86 (d, J=8.7 Hz, 0.5H), 6.63 (dd, J=14.3, 8.5 Hz, 1H),5.94 (dd, J=8.2, 2.4 Hz, 0.5H), 5.87-5.79 (m, 0.5H), 4.90-4.72 (m, 1H),4.49-4.42 (m, 2H), 4.11-3.97 (m, 1H), 3.65-3.45 (m, 1H), 3.23-3.05 (m,3H), 2.86-2.54 (m, 2H), 2.50 (p, J=1.8 Hz, 2H), 2.39 (m+d, J=4.1 Hz,4H), 2.34-2.25 (m, 1H), 2.21 (d, J=3.8 Hz, 3H), 2.11 (d, J=18.1 Hz, 1H),1.99 (m, 1H).

Example 94:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D10)

A solution of Intermediate C10 (1.97 g, 5.41 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (2.26 g, 5.95 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (0.768 g, 5.95 mmol) and TEA(2.26 mL, 16.22 mmol) in DMF (20 mL) was stirred at room temperature for3 h. The mixture was partitioned between ethyl acetate (200 mL) andwater (100 mL), then the layers separated. The organic phase was washedwith water (100 mL), passed through a PhaseSep© cartridge and evaporatedin vacuo to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D10 (1.92 g, 68%), which was used without furtherpurification; Rt 1.55 min (method 1), m/z 476 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E10)

A solution of Intermediate D10 (1.92 g, 4.04 mmol) in acetic acid (5 mL)was heated to 80° C. for 48 h then left to cool to rt. The reactionmixture was passed on to FL for workup and purification. The reactionmixture was concentrated in vacuo to give a beige solid. MeOH (5 mL) wasadded followed by DCM (5 mL). The beige suspension was filtered througha PhaseSep© cartridge. The solid was washed with MeOH (4 mL) followedwith diethyl ether (10 mL). The solid was dissolved in DCM (100 mL)washed with saturated aqueous sodium bicarbonate solution (2×50 mL). Theorganic was washed with water (100 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E10 (0.798 g, 41%) as a white solid; Rt 1.34 min (method1), m/z 458 (M+H)+ (ES+).

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (0.017 ml,0.115 mmol), Intermediate E10 (0.050 g, 0.109 mmol) and(3,4-dichlorophenyl)boronic acid (0.023 g, 0.120 mmol) in acetonitrile(3.31 ml, 63.4 mmol) with stirring for 15 h at 40° C. The reactionmixture is a grey suspension. DCM (1.5 mL) was added to the reactionmixture. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(33 mg, 48%) as a yellow solid; Rt 2.19 min (method 1), m/z 602 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.03 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.5 Hz,1H), 7.61 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.40 (dd, J=8.9,2.6 Hz, 1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 6.17 (d, 1H), 4.82-4.69 (m,1H), 3.87-3.79 (m, 2H), 3.13-2.99 (m+s, 5H), 2.81-2.51 (m, 4H), 2.36 (s,3H), 2.19 (s, 3H), 2.15-2.07 (m, 2H), 2.06-1.96 (m, 2H).

Example 95:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL,0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and(4-chloro-3-fluorophenyl)boronic acid (20.96 mg, 0.120 mmol) inacetonitrile (3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (36 mg, 55%)as a white solid; Rt 2.08 min (method 1), m/z 587 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.85 (dd, J=12.1, 2.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.60(d, J=1.6 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.24 (dd, J=9.0, 2.5, 1.1 Hz,1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 6.14 (d, J=7.9 Hz, 1H), 4.77-4.72 (m,1H), 3.83 (d, J=12.1 Hz, 2H), 3.13-2.98 (m+s, 5H), 2.79-2.59 (m, 2H),2.58-2.43 (m, 2H), 2.36 (s, 3H), 2.19 (s, 3H), 2.15-2.00 (m, 3H).

Example 96:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL,0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (22.41 mg, 0.120 mmol) inacetonitrile (3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (33.8 mg, 51%)as a white solid; Rt 1.90 min (method 1), m/z 598 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.79 (d, J=2.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.63 (d,J=1.6 Hz, 1H), 7.28 (dd, J=9.0, 2.6 Hz, 1H), 7.19 (dd, J=8.5, 1.7 Hz,1H), 7.08 (d, J=9.1 Hz, 1H), 6.07 (dd, J=8.1, 2.2 Hz, 1H), 4.82-4.70 (m,1H), 3.81 (m, 2H), 3.77 (s, 3H), 3.10-2.96 (m+s, 5H), 2.77 (dt, 1H),2.69-2.53 (m, 2H), 2.50-2.39 (m, 2H), 2.37 (s, 3H), 2.24-2.11 (m+s, 4H),2.03-1.95 (m, 1H), 1.80-1.70 (m, 1H).

Example 97:(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL,0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and(2,3-dihydrobenzofuran-5-yl)boronic acid (19.71 mg, 0.120 mmol) inacetonitrile (3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by flash chromatography on theCompanion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(32 mg, 50%) as a white solid; Rt 1.75 min (method 1), m/z 576 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.70 (d, J=8.5 Hz, 1H), 7.65 (d, J=1.6 Hz,1H), 7.39-7.36 (m, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 7.05 (dd, J=8.5,2.4 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 5.94 (dd, J=8.2, 2.7 Hz, 1H),4.73-4.63 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.77 (t, J=14.9 Hz, 2H), 3.10(t, J=8.7 Hz, 2H), 3.02 (s, 3H), 3.00-2.90 (m, 2H), 2.78 (dt, 1H),2.70-2.56 (m, 1H), 2.46-2.31 (m+s, 5H), 2.26-2.16 (m+s, 4H), 1.99-1.90(m, 1H), 1.52-1.44 (m, 1H).

Example 98:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μl,0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and(3,4-difluorophenyl)boronic acid (18.98 mg, 0.120 mmol) in acetonitrile(3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15 h at 40° C.The mixture was concentrated under reduced pressure. The residue wastaken up in the minimum of DCM, passed through a syringe filter and thesolution then purified by chromatography on the Companion (4 g column,0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(41.9 mg, 66%) as a beige solid; Rt 2.00 min (method 1), m/z 570 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.7 Hz, 1H), 7.74 (d,J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.38 (dt, J=10.6, 9.2 Hz, 1H),7.22-7.14 (m, 2H), 6.10 (dd, J=8.2, 1.9 Hz, 1H), 4.80-4.65 (m, 1H), 3.82(d, J=11.7 Hz, 2H), 3.11-2.93 (m+s, 5H), 2.78-2.59 (m, 2H), 2.58-2.43(m, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 2.14-2.06 (m, 1H), 2.05-1.90 (m,2H).

Example 99:(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μl,0.115 mmol), Intermediate E10 (50 mg, 0.109 mmol) and(3-chloro-4-fluorophenyl)boronic acid (20.96 mg, 0.120 mmol) inacetonitrile (3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(4 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (35.5 mg, 54%)as a beige solid; Rt 2.03 min (method 1), m/z 586 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.99-7.90 (m, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=1.6Hz, 1H), 7.42-7.32 (m, 2H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 6.12 (dd,J=8.1, 1.9 Hz, 1H), 4.81-4.68 (m, 1H), 3.82 (d, J=11.8 Hz, 2H),3.11-2.96 (m+s, 5H), 2.81-2.59 (m, 2H), 2.58-2.41 (m, 3H), 2.36 (s, 3H),2.19 (s, 3H), 2.16-2.07 (m, 1H), 2.06-1.97 (m, 1H), 1.95-1.85 (m, 1H).

Example 100:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μl,0.115 mmol Intermediate E10 (50 mg, 0.109 mmol) and(3-fluoro-4-methoxyphenyl)boronic acid (20.43 mg, 0.120 mmol) inacetonitrile (3310 μL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15h at 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by chromatography on the Companion(4 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (36.4 mg,55%) as a beige solid; Rt 1.85 min (method 1), m/z 582 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H), 7.64-7.57 (m, 2H), 7.18 (dd,J=8.5, 1.7 Hz, 1H), 7.12-7.04 (m, 2H), 6.03 (dd, J=8.3, 2.1 Hz, 1H),4.79-4.67 (m, 1H), 3.86-3.76 (m, 2H), 3.75 (s, 3H), 3.09-2.97 (m+s, 5H),2.81-2.69 (m, 1H), 2.69-2.56 (m, 1H), 2.57-2.40 (m, 3H), 2.36 (s, 3H),2.20 (s, 3H), 2.16-2.08 (m, 1H), 2.00-1.97 (m, 1H), 1.84-1.74 (m, 1H).

Example 101:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D11)

A solution of Intermediate C11 (450 mg, 1.566 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (222 mg, 1.723 mmol), HATU (655mg, 1.723 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (222 mg, 1.723mmol) and TEA (655 μL, 4.70 mmol) in DMF (121 μl, 1.566 mmol) wasstirred at room temperature for 15 h. The mixture was partitionedbetween ethyl acetate (200 mL) and water (100 mL), then the layersseparated. The organic phase was washed with brine (100 ml),concentrated in vacuo to give a crude purple mixture. The crude productwas purified by chromatography on the Companion (12 g column, 0-10%MeOH/DCM) to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide Intermediate D11 (57mg, 9%) as a white sticky solid; Rt 1.31 min (method 1), m/z 399 (M+H)+(ES+); More product was obtained from the aqueous layer by concentrationin vacuo. The resulting solid was washed with DCM (2×50 mL) and MeOH (50mL). The organics were combined and concentrated in vacuo. The yellowresidue was loaded on SCX resin (capture and release) to give 659 mg ofa yellow green sticky solid, which was purified by flash chromatography(12 g, Companion, DCM/10% MeOH in DCM from 100/0 to 0/100) to give themajor crop of(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentypamino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D11 (334 mg, 0.830 mmol, 53.0% yield) was isolated as awhite colorless glass; Rt 1.31 min (method 1), m/z 399 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E11)

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentypamino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D11 (391 mg, 0.981 mmol) was dissolved in acetic acid (3932μL, 68.7 mmol) and stirred at 80° C. for 15 h. The mixture wasconcentrated under reduced pressure then redissolved in methanol (20mL). Solid potassium carbonate (1.5 g) was added and the mixture wasstirred for 1 h. Filtering the suspension was difficult so it wasconcentrated in vacuo/pre-adsorbed on silica gel. The crude product waspurified by chromatography on the Companion (4 g column, 5-15% MeOH/DCM)to give(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(140 mg, 36%) was isolated as a white solid; Rt 1.13 min (method 1), m/z381 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (8.39 mg, 0.018 mmol) was added to a solution of DBU (19.14 μL,0.127 mmol), Intermediate E11 (46 mg, 0.121 mmol) and(4-chloro-3-fluorophenyl)boronic acid (23.19 mg, 0.133 mmol) inacetonitrile (4 mL) with stirring for 18 hrs at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-5% MeOH inDCM, gradient elution) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dirnethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(46 mg, 42%) as an off-white solid; Rt 1.97 min (method 1), m/z 508(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.81 (td, J=12.1, 2.5 Hz, 1H),7.62-7.55 (m, 2H), 7.51 (td, J=8.7, 2.2 Hz, 1H), 7.35-7.23 (m, 1H), 7.17(dt, J=8.5, 2.1 Hz, 1H), 6.14 (dd, J=37.6, 7.5 Hz, 1H), 5.34-5.25 (m,1H), 4.89 (dd, J=3.6, 1.5 Hz, 1H), 4.50 (s, 1H), 2.69 (m, 1H), 2.56 (m,1H), 2.36 (d, J=1.1 Hz, 3H), 2.31-2.27 (m, 4H), 2.19 (d, J=1.0 Hz, 3H),2.15-2.04 (m, 3H), 1.76 (d, J=9.5 Hz, 1H).

Example 102:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.39 mg, 0.018 mmol) was added to a solution of DBU (19.14 μl,0.127 mmol), Intermediate E11 (46 mg, 0.121 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (24.79 mg, 0.133 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-5% MeOH inDCM, gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(26 mg, 41%) as an light yellow solid; Rt 1.77 min (method 1), m/z 521(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.74 (dd, J=20.7, 2.6 Hz, 1H),7.65-7.52 (m, 2H), 7.32 (ddd, J=11.8, 9.0, 2.6 Hz, 1H), 7.16 (ddd,J=8.5, 3.0, 1.6 Hz, 1H), 7.07 (dd, J=9.1, 2.8 Hz, 1H), 6.04 (dd, J=7.4,7.7 Hz, 1H), 5.29 (m, 1H), 4.88 (t, J=3.2 Hz, 1H), 4.48 (s, 1H), 3.76(d, J=0.7 Hz, 3H), 2.76-2.55 (m, 1H), 2.37 (d, J=0.9 Hz, 3H), 2.30-2.25(m, 5H), 2.20 (d, J=0.9 Hz, 3H), 2.12-2.05 (m, 2H), 1.97 (dd, J=14.6,7.2 Hz, 1H), 1.74 (d, J=6.2 Hz, 1H).

Example 103:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL,0.115 mmol), Intermediate E11 (50 mg, 0.109 mmol) and(3,4-difluorophenyl)boronic acid (18.98 mg, 0.120 mmol) in acetonitrile(3310 μl, 63.4 mmol) and DCM (1.5 mL) with stirring for 15 h at 40° C.The mixture was concentrated under reduced pressure. The residue wastaken up in the minimum of DCM, passed through a syringe filter and thesolution then purified by chromatography on the Companion (4 g column,0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (69.3 mg, 38%) as abeige solid; Rt 2.04 min (method 1), m/z 525 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.97 (dd, J=19.0, 2.5 Hz, 1H), 7.65-7.53 (m, 3H), 7.46(ddd, J=14.9, 9.0, 2.6 Hz, 1H), 7.17 (ddd, J=8.3, 2.8, 1.6 Hz, 1H), 6.17(dd, J=38.2, 7.2 Hz, 1H), 5.31 (h, J=8.7 Hz, 1H), 4.90 (dd, J=3.4, 1.0Hz, 1H), 4.56-4.45 (m, 1H), 2.78-2.61 (m, 2H), 2.61-2.46 (m, 1H),2.43-2.21 (m+s, 5H), 2.19 (d, J=1.0 Hz, 3H), 2.17-1.95 (m, 2H),1.81-1.70 (m, 1H).

Example 104:(1R,3R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate

Intermediate D11 (1.35 g, 3.39 mmol) was dissolved in acetic acid (5 mL)and stirred at 80° C. for 18 hrs. The reaction mixture was cooled to RTand the solvent was removed in vacuo. The residue was purified bychromatography (24 g silica, 0-10% methanol in DCM, gradient elution).Fractions containing(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate were combined and concentrated in vacuo to afford(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate (354 mg, 26%) as a white solid; Rt 1.37 mn (method 1), m/z 423(M+H)+ (ES+).

(1R,3R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate

CuTMEDA (8.24 mg, 0.018 mmol) was added to a solution of DBU (0.019 mL,0.124 mmol),(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate (50 mg, 0.118 mmol) and (3,4-difluorophenyl)boronic acid (20.56mg, 0.130 mmol) in acetonitrile (3.585 mL, 68.6 mmol) with stirring for15 h at 40° C. The reaction mixture was cooled down to RT, and themixture filtered and then purified by flash chromatography on theCompanion (4 g column, 0-10% MeOH in DCM, gradient elution) to afford(1R,3R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate (40 mg, 60%) as a colorless glass; Rt 2.12 min (method 1), m/z535 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.86-7.76 (m, 1H), 7.68 (dd,J=8.5, 4.1 Hz, 1H), 7.62 (t, J=2.0 Hz, 1H), 7.44-7.32 (m, 1H), 7.29-7.13(m, 2H), 6.17-6.07 (m, 1H), 5.46-5.35 (m, 1H), 5.31-5.15 (m, 1H),2.78-2.44 (m, 5H), 2.37 (d, 3H), 2.30-2.20 (m, 2H), 2.20 (d, J=1.5 Hz,3H), 2.18-2.05 (m+d, 5H), 1.92-1.80 (m, 1H).

Example 105:(1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate(1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate

CuTMEDA (8.24 mg, 0.018 mmol) was added to a solution of DBU (0.019 mL,0.124 mmol),(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate (50 mg, 0.118 mmol) and (3-chloro-4-methoxyphenyl)boronic acid(24.27 mg, 0.130 mmol) in acetonitrile (3.58 mL, 68.6 mmol) withstirring for 15 h at 40° C. The reaction mixture was cooled down to RT,and the mixture was filtered and then purified by chromatography on theCompanion (12 g column, 0-10% MeOH in DCM, gradient elution) to afford(1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate (19.1 mg, 27% yield) as a beige solid; Rt 2.06 min (method 1),m/z 563 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.74 (dd, J=22.2, 2.6 Hz, 1H),7.66 (dd, J=8.5, 3.6 Hz, 1H), 7.63 (dd, J=3.2, 1.6 Hz, 1H), 7.29 (ddd,J=26.2, 9.0, 2.6 Hz, 1H), 7.20-7.15 (m, 1H), 7.06 (dd, J=9.1, 4.7 Hz,1H), 6.08 (dd, 1H), 5.42-5.34 (m, 1H), 5.24 (h, J=9.3 Hz, 1H), 3.76 (d,3H), 2.80-2.57 (m, 2H), 2.56-2.41 (m, 3H), 2.37 (d, J=1.9 Hz, 3H),2.26-2.09 (m+d, 6H), 2.08 (s, 3H), 2.04-1.94 (m, 1H), 1.89-1.75 (m, 1H).

Example 106:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one4-(3,5-dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-methoxycyclopentyl)-2-nitroaniline

Trans-(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol(815 mg, 2.57 mmol) is dissolved in THF (1.62E+04 μL, 198 mmol). Thissolution is cooled to 0° C., then 18-CROWN-6 (45.8 mg, 0.173 mmol) indry THF (0.1 mL) was added followed with NaH (60% in oil) (113 mg, 2.83mmol). After 15 mn of stirring, METHYL IODIDE (177 μL, 2.83 mmol) isadded. The reaction was allowed to warm up to RT overnight. After 15 h,NaH (40 mg) was added at 0° C. then the reaction was stirred for 1 hbefore methyl iodide (18 μL) was added. 18-CROWN-6 (75 mg) was added.After 20 mn, more methyl iodide (18 μL) was added. The reaction wasstirred overnight and then saturated aqueous ammonium chloride (10 mL)was added, followed by DCM (2×5 mL) in a separating funnel and theorganic layer was dried (MgSO₄), filtered, evaporated, and concentratedto give an orange sticky gum, which was purified by flash chromatography(24 g, DCM/MeOH: 100/0 to 90/10) to give4-(3,5-dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-methoxycyclopentyl)-2-nitroaniline(481 mg, 55%) as a red orange glass; Rt 2.36 min (method 1), m/z 332(M+H)+ (ES+).

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

HATU (550 mg, 1.445 mmol) was added to a solution of4-(3,5-dimethylisoxazol-4-yl)-N¹-(trans-(1r,3r)-3-methoxycyclopentyl)benzene-1,2-diamine(363 mg, 1.108 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (171 mg,1.325 mmol) and DIPEA (0.316 mL, 1.806 mmol) in DMF (3.357 mL, 43.4mmol) then stirred at room temperature for 18 h. The mixture waspartitioned between ethyl acetate (100 mL) and water (100 mL), then thelayers separated. The organic phase was washed with brine (100 ml),concentrated in vacuo to give a crude pink oil (693 mg). The crudeproduct was purified by chromatography on the Companion (12 g column,0-10% MeOH/DCM) to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(0.42 g, 82%) as a colourless foam; Rt 1.58 min (method 1), m/z 413(M+H)+ (ES+).

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(0.42 g, 0.988 mmol) was dissolved in acetic acid (3.96 ml, 69.1 mmol)and stirred at 70° C. for 15 h. The mixture was concentrated in vacuo.The crude brown oil was purified by flash chromatography (4 g, DCM/MeOH:100/0 to 90/10) to give(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (202 mg, 48%) was isolated as a pinkfoam; Rt 1.38 min (method 1), m/z 395 (M+H)+ (ES+).

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μl,0.133 mmol),(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.127 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (26.0 mg, 0.139 mmol) inacetonitrile (3840 μL, 73.5 mmol) with stirring for 22 h at 40° C. Themixture was concentrated under reduced pressure. The residue was takenup in the minimum of DCM, passed through a syringe filter and thesolution then purified by chromatography on the Companion (4 g column,0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(41 mg, 57%) as a greenish solid; Rt 2.10 min (method 1), m/z 535 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.74 (dd, J=25.9, 2.6 Hz, 1H), 7.65-7.57 (m,2H), 7.31 (ddd, J=15.8, 8.9, 2.6 Hz, 1H), 7.16 (ddd, J=8.4, 2.8, 1.7 Hz,1H), 7.07 (dd, J=9.1, 3.3 Hz, 1H), 6.07 (ddd, 1H), 5.24-5.11 (m, 1H),4.19-4.08 (m, 1H), 3.76 (d, J=1.5 Hz, 3H), 3.27 (s, 3H), 2.78-2.56 (m,2H), 2.37 (d, J=1.6 Hz, 3H), 2.36-2.25 (m, 2H), 2.20 (d, J=1.6 Hz, 3H),2.18-2.03 (m, 5H), 1.90-1.78 (m, 1H).

Example 107:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol),(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.127 mmol) and (3,4-dichlorophenyl)boronic acid (26.6 mg, 0.139mmol) in acetonitrile (3840 μL, 73.5 mmol) with stirring for 22 h at 40°C. The mixture was concentrated under reduced pressure. The residue wastaken up in the minimum of DCM, passed through a syringe filter and thesolution then purified by chromatography on the Companion (4 g column,0-10% MeOH in DCM, gradient elution) to afford(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (44 mg, 62%) as abeige foam; Rt 2.37 min (method 1), m/z 539 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.98 (dd, J=16.4, 2.6 Hz, 1H), 7.67-7.59 (m, 2H), 7.56 (dd,J=8.9, 3.5 Hz, 1H), 7.45 (ddd, J=11.7, 8.9, 2.6 Hz, 1H), 7.22-7.14 (m,1H), 6.19 (dd, J=25.2, 7.6 Hz, 1H), 5.25-5.16 (m, 1H), 4.24-4.07 (m,1H), 3.29 (d, 3H), 2.79-2.59 (m, 2H), 2.58-2.45 (m, 1H), 2.44-2.28 (m+d,6H), 2.27-2.11 (m+d, 5H), 2.10-2.00 (m, 1H), 1.94-1.79 (m, 1H).

Example 108:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL,0.133 mmol),(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.127 mmol) and (4-chloro-3-fluorophenyl)boronic acid (24.31 mg,0.139 mmol) in acetonitrile (3840 μL, 73.5 mmol) with stirring for 15 hat 40° C. The mixture was concentrated under reduced pressure. Theresidue was taken up in the minimum of DCM, passed through a syringefilter and the solution then purified by flash chromatography on theCompanion (4 g column, 0-10% MeOH in DCM, gradient elution) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(47.8 mg, 68%) as a beige solid; Rt 2.25 min (method 1), m/z 523 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.81 (ddd, J=12.1, 7.6, 2.5 Hz, 1H), 7.63(dd, J=8.5, 4.0 Hz, 1H), 7.60 (t, J=2.0 Hz, 1H), 7.51 (td, J=8.8, 3.4Hz, 1H), 7.33-7.24 (m, 1H), 7.18 (dt, J=8.4, 2.0 Hz, 1H), 6.17 (dd,J=26.0, 7.8 Hz, 1H), 5.25-5.14 (m, 1H), 4.21-4.10 (m, 1H), 3.29 (d, 3H),2.78-2.59 (m, 2H), 2.59-2.50 (m, 1H), 2.47-2.25 (m+d, 6H), 2.26-2.11(m+d, 5H), 2.11-2.01 (m, 1H), 1.92-1.80 (m, 1H).

Example 110:(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)—N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (Intermediate D12)

HATU (600 mg, 1.578 mmol) was added to a stirred solution of TEA (0.25ml, 1.794 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (250 mg, 1.936mmol) and Intermediate C12 (500 mg, 1.400 mmol) in N,N-dimethylformamide(5 mL) then the mixture was stirred at room temperature for 18 h. Themixture was diluted with water (40 mL) then extracted with ethyl acetate(2×40 mL). The combined organic phases were washed with 20% brine (2×40mL) then saturated brine (40 mL). The organic phase was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude product waspurified by chromatography on the Companion (40 g column, 0-50% THF/DCM)then triturated in diethyl ether to afford(S)—N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(605 mg, 99%) as a white solid; Rt 1.86 min (method 1), m/z 433 (M+H)+(ES+).

(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E12)

Intermediate D12 (605 mg, 1.385 mmol) was heated to 80° C. in aceticacid (15 mL) for 2 h. The bulk of the solvents were removed underreduced pressure then the residue (ca. 1 mL) was added slowly to astirred solution of 1 M aqueous sodium carbonate (50 mL). The resultingsolid was collected by filtration then was purified by chromatography onthe Companion (40 g column, 15-75% THF/DCM) then triturated in diethylether to afford(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E12 (420 mg, 72%) as a white solid; Rt 1.70 min (method 1),m/z 415 (M+H)+ (ES+).

4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole

CuTMEDA (55 mg, 0.118 mmol) was added to a stirred solution ofIntermediate E12 (100 mg, 0.239 mmol) in pyridine (3 mL) then themixture was stirred for 15 min at 40° C. (3,4-difluorophenyl)boronicacid (100 mg, 0.633 mmol) was added then the mixture was heated to 40°C. for 2 h. The mixture was diluted with ethyl acetate (25 mL) thenwashed with water (3×25 mL) and saturated brine (25 mL). The organicphase was dried (MgSO₄), filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography on theCompanion (12 g column, 0-25% THF) then triturated in diethyl ether to(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(106 mg, 83%) as a white solid; Rt 2.32 min; m/z 527 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.84 (1H, ddd, J=13.2, 7.4, 2.7 Hz), 7.62 (1H, d, J=1.6Hz), 7.59 (1H, d, J=8.5 Hz), 7.38 (1H, dt, J=10.5, 9.2 Hz), 7.22 (1H,dd, J=8.5, 1.7 Hz), 7.20-7.12 (1H, m), 6.06 (1H, d, J=8.1 Hz), 4.81 (1H,s), 2.80-2.58 (2H, m), 2.60-2.52 (1H, m), 2.43 (2H, s), 2.36 (3H, s),2.30-2.21 (4H, m), 2.19 (3H, s), 2.17-2.08 (1H, m), 2.07-1.98 (1H, m),1.98-1.89 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=4.13 min (5.65 min minor), ˜90% ee @ 254 nm.

Example 111:(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.027 ml, 0.181 mmol) was added to a solution of Intermediate E12(50 mg, 0.121 mmol) in MeCN (2 ml, 38.3 mmol), and stirred for 10 min.CuTMEDA (11.21 mg, 0.024 mmol) was added, sonicated and stirred for a 10min, (3-chloro-4-methoxyphenyl)boronic acid (33.7 mg, 0.181 mmol) addedand the reaction stirred at RT for 18 hr. The mixture was concentratedunder reduced pressure then the crude product was purified bychromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (36 mg, 53%) as a tan solid; Rt 2.26 min;m/z 555 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78 (1H, d, J=2.6 Hz), 7.63(1H, d, J=1.6 Hz), 7.57 (1H, d, J=8.5 Hz), 7.26 (1H, dd, J=9.0, 2.7 Hz),7.21 (1H, dd, J=8.5, 1.7 Hz), 7.07 (1H, d, J=9.1 Hz), 6.08-5.98 (2H, m),4.89-4.77 (1H, m), 3.76 (3H, s), 2.84-2.70 (1H, m), 2.70-2.58 (1H, m),2.48-2.39 (2H, m), 2.37 (3H, s), 2.29-2.21 (4H, m), 2.20 (3H, s),2.18-2.12 (1H, m), 2.04-1.93 (1H, m), 1.75-1.66 (1H, m); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 ml/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=5.37 min (7.89 minor),˜90% ee @ 254 nm.

112:(S)-1-(3-fluoro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.027 ml, 0.181 mmol) was added to a solution of Intermediate E12(50 mg, 0.121 mmol) in MeCN (2 ml, 38.3 mmol), and stirred for 10 min.CuTMEDA (11.21 mg, 0.024 mmol) was added, sonicated and stirred for a 10min, (3-fluoro-4-methoxyphenyl)boronic acid (30.8 mg, 0.181 mmol) addedand the reaction stirred at RT for 18 hr. The mixture was concentratedunder reduced pressure then the crude product was purified bychromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(44 mg, 67%) as a pink solid; Rt 2.20 min; m/z 539 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.65-7.54 (3H, m), 7.22 (1H, dd, J=8.5, 1.7 Hz), 7.14-7.05(2H, m), 6.00 (1H, dd, J=8.6, 1.7 Hz), 4.81 (1H, s), 3.75 (3H, s),2.82-2.69 (1H, m), 2.70-2.57 (1H, m), 2.46-2.38 (2H, m), 2.37 (3H, s),2.30-2.21 (4H, m), 2.20 (3H, s), 2.18-2.10 (2H, m), 2.05-1.92 (1H, m),1.82-1.70 (1H, m). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=5.54 min (7.90 min minor), ˜90% ee @ 254 nm.

Example 113:(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-methyltetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D13)

HATU (1.791 g, 4.71 mmol) was added to a solution of 4 Intermediate C13(1.45 g, 4.28 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.608 g,4.71 mmol) and N,N-diisopropylethylamine (0.897 mL, 5.14 mmol) in DMF (8mL, 103 mmol) then stirred at room temperature overnight. The mixturewas diluted with water (20 mL) then extracted with ethyl acetate (3×40mL). The combined organic phases were washed with 1M aqueous HCl (10mL), saturated aqueous NaHCO3 (10 mL) and saturated brine (3×10 mL),then dried (MgSO₄), filtered and concentrated to give a brown oil, whichwas purified by flash chromatography (40 g column, 0-10% MeOH/DCM) toafford Intermediate D13 (1.63 g, 3.91 mmol, 91%) as a white foam; Rt1.61 min; m/z 413 (M+H)+ (ES+); 1H NMR (d6-DMSO) consistent with productstructure as a mixture of diastereomers (ratio ˜9:1) at >95% purity

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E13)

Intermediate D13 (1.60 g, 3.88 mmol) was heated to 80° C. in ACETIC ACID(8.88 ml, 155 mmol) for 20 h. After cooling to RT, the mixture wasconcentrated under reduced pressure. The reaction mixture was dilutedwith MeOH (30 mL) and solid potassium carbonate (1 g) was added. Themixture was stirred for 1 h before concentrating onto loose silica gel.The crude product was purified by flash chromatography on silica gel (40g column, 0-10% (0.7 M Ammonia/MeOH)/DCM) to afford(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E13 (970 mg, 63%) as a tanned solid; Rt 1.36 min; m/z 395(M+H)+ (ES+).

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.042 ml, 0.279 mmol) was added to a solution of Intermediate E13(50 mg, 0.127 mmol) in MeCN (2 ml, 38.3 mmol), and stirred for 10 min.CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for a 10min, then (3,4-difluorophenyl)boronic acid (40.0 mg, 0.254 mmol) addedand the reaction stirred at RT for 18 h. The mixture was concentratedunder reduced pressure then the crude product was purified bychromatography on silica gel (12 g column, 0-10% MeOH/DCM) to afford(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(54 mg, 83%) as a light pink solid; Rt 2.03 min; m/z 507 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: NMR consistent as a mixture of 4 diastereoisomers.

Example 114:(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.042 ml, 0.279 mmol) was added to a solution of Intermediate E13(50 mg, 0.127 mmol) in MeCN (2 ml, 38.3 mmol), and stirred for 10 min.CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for a 10min, then boronic acid added and the reaction stirred at RT for 18 hr.The mixture was concentrated under reduced pressure then the crudeproduct was purified by chromatography on silica gel (24 g column, 0-10%MeOH/DCM) to afford(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(48 mg, 0.089 mmol, 70%) as a tan solid; Rt 1.98 min; m/z 535 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: NMR consistent as a mixture of 4diastereoisomers.

Example 115:(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

DBU (0.042 ml, 0.279 mmol) was added to a solution of Intermediate E13(50 mg, 0.127 mmol) in MeCN (2 ml, 38.3 mmol), and stirred for 10 min.CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for a 10min, then (3-fluoro-4-methoxyphenyl) boronic acid (43.1 mg, 0.254 mmol)added and the reaction stirred at RT for 18 hr. The mixture wasconcentrated under reduced pressure then the crude product was purifiedby chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(39 mg, 59%) as a pink solid; Rt 1.91 min; m/z 519 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: NMR consistent as a mixture of 4 diastereoisomers.

Example 118:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (Intermediate D15)

HATU (750 mg, 1.972 mmol) was added to a stirred solution of TEA (0.3mL, 2.152 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.25 g, 1.936mmol) and Intermediate C15 (574 mg, 1.820 mmol) in N,N-dimethylformamide(10 mL) then the mixture was stirred at room temperature for 2 h. Themixture was diluted with brine (100 mL) then extracted with ethylacetate (3×100 mL). The combined organic phases were concentrated underreduced pressure. The crude product was purified by chromatography onthe Companion (40 g column, 50-100% THF/DCM) then triturated in diethylether to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (773 mg, 95% yield) as a pale pink solid; Rt1.58 min; m/z 427 (M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Intermediate E15)

Intermediate D15 (750 mg, 1.758 mmol) was heated to 80° C. in aceticacid (15 mL) for 1.5 h. The solvents were removed under reduced pressurethen the mixture was dissolved in dichloromethane (50 mL) anddiethylamine (6 mL) and concentrated onto loose silica gel. The silicatewas purified by chromatography on the Companion (40 g column, 50-75%THF/DCM) then triturated in diethyl ether (15 mL) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E15 (550 mg, 76%) as a white solid; Rt 1.19 min; m/z 409(M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (10 mg, 0.022 mmol) was added to a stirred suspensionIntermediate E15 (70 mg, 0.171 mmol) and DBU (28 μL, 0.186 mmol) inacetonitrile (6 mL). (3,4-Difluorophenyl)boronic acid (30 mg, 0.190mmol) was added and the mixture was heated to 70° C. for 3 h. Thevolatiles were removed under reduced pressure then the residue wasdissolved in THF, filtered and adsorbed onto loose silica gel.Purification by chromatography on the Companion (12 g column, 0-50%THF/DCM) then triturated in diethyl ether to give(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (47 mg, 52.2%yield) as a beige solid; Rt 1.92 min; m/z 521 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.83 (ddd, J=13.2, 7.4, 2.6 Hz, 1H), 7.76 (d, J=8.5 Hz,1H), 7.61 (d, J=1.6 Hz, 1H), 7.39 (dd, J=10.7, 9.2 Hz, 1H), 7.23 (dd,J=8.4, 1.7 Hz, 1H), 7.19-7.13 (m, 1H), 6.08 (dd, J=8.1, 2.0 Hz, 1H),4.52 (tt, 1H), 4.47 (s, 1H), 2.82-2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s,3H), 2.13-2.03 (m, 1H), 1.79-1.50 (m, 6H), 1.23 (s, 3H).

Example 119:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

Intermediate E15 (70 mg, 0.170 mmol), (3-fluoro-4-methoxyphenyl)boronicacid (30 mg, 0.177 mmol), CuTMEDA (10 mg, 0.022 mmol) and DBU (26 μL,0.172 mmol) in acetonitrile (3 mL) was heated to 70° C. for 2 h. Themixture was concentrated onto loose silica gel. The silicate waspurified by chromatography on the Companion (4 g column, 5-50% THF/DCM)then triturated in diethyl ether to yield(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (43 mg, 47%) as a white solid; Rt 1.78 min; m/z 533(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.74 (d, J=8.5 Hz, 1H), 7.66-7.54 (m,2H), 7.22 (dd, J=8.5, 1.3 Hz, 1H), 7.14-7.01 (m, 2H), 6.01 (d, J=7.9 Hz,1H), 4.62-4.32 (m, 2H), 3.75 (s, 3H), 2.84-2.70 (m, 1H), 2.70-2.52 (m,4H), 2.38 (s, 3H), 2.21 (s, 3H), 2.15-2.06 (m, 1H), 1.80-1.66 (m, 2H),1.66-1.51 (m, 3H), 1.48-1.37 (m, 1H), 1.22 (s, 3H).

Example 120:(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A mixture of Intermediate E15 (70 mg, 0.170 mmol),(3,4-dichlorophenyl)boronic acid (35 mg, 0.183 mmol), CuTMEDA (10 mg,0.022 mmol) and DBU (26 μl, 0.172 mmol) in acetonitrile (3 mL) washeated to 70° C. for 2 h. The mixture was concentrated onto loose silicagel. The silicate was purified by chromatography on the Companion (4 gcolumn, 5-50% THF/DCM) then triturated in ethyl ether to yield(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (49 mg, 50%) as a white solid; Rt 2.14 min; m/z 553(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.76 (d, J=8.5Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.41 (dd,J=8.9, 2.6 Hz, 1H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 6.14 (d, J=8.3 Hz,1H), 4.63-4.51 (m, 1H), 4.48 (s, 1H), 2.84-2.53 (m, 5H), 2.38 (s, 3H),2.21 (s, 3H), 2.13-2.02 (m, 1H), 1.81-1.51 (m, 6H), 1.24 (s, 3H).

Example 121:(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A mixture of Intermediate E15 (70 mg, 0.170 mmol),(4-chloro-3-fluorophenyl)boronic acid (32 mg, 0.184 mmol), CuTMEDA (10mg, 0.022 mmol) and DBU (26 μl, 0.172 mmol) in acetonitrile (3 mL) washeated to 70° C. for 2 h. The mixture was concentrated onto loose silicagel. The silicate was purified by chromatography on the Companion (4 gcolumn, 5-50% THF/DCM) then triturated in diethyl ether to yield((S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(38 mg, 40%) as a white solid; Rt 2.06 min; m/z 537 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.84 (dd, J=12.1, 2.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.60(d, J=1.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.28-7.19 (m, 2H), 6.13 (d,J=7.8 Hz, 1H), 4.61-4.48 (m, 1H), 4.44 (br s, 1H), 2.82-2.52 (m, 5H),2.37 (s, 3H), 2.21 (s, 3H), 2.12-2.03 (m, 1H), 1.81-1.52 (m, 6H), 1.24(s, 3H).

Example 122:(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)—N-(2-(2-oxaspiro[3.3]heptan-6-ylamino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D16)

A solution of Intermediate C16 (1.47 g, 4.91 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouroniumhexafluorophosphate(V) (2.054 g, 5.40 mmol),(S)-5-oxopyrrolidine-2-carboxylic acid (0.697 g, 5.40 mmol) and TEA(2.053 mL, 14.73 mmol) in DMF (20 mL) was stirred at room temperaturefor 2 h. The mixture was partitioned between ethyl acetate (200 mL) andwater (100 mL), then the layers separated. The organic phase was washedwith brine (100 ml), dried (MgSO₄) and concentrated in vacuo to give apurple oil. Intermediate D16 (1.6 g, 3.04 mmol) was used in thesubsequent step without further purification; Rt 1.53 min; m/z 411(M+H)+ (ES+).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (Intermediate E16)

Intermediate D16 was dissolved in acetic acid (6 mL) and stirred at 80°C. for 18 hrs. The reaction mixture was cooled to RT and the solvent wasremoved in vacuo. The residue was purified by chromatography (24 gsilica, 0-10% methanol in DCM, gradient elution). Fractions containingthe product were combined and concentrated in vacuo. to give the crude(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneIntermediate E16 (ca 206 mg, 13%); Rt 1.53 min; m/z 411 (M+H)+ (ES+).

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (17.75 mg, 0.038 mmol) was added to a solution of DBU (40.3 μl,0.268 mmol), Intermediate E16 (100 mg, 0.255 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (52.2 mg, 0.280 mmol) inacetonitrile (4 ml) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(53 mg, 38%) as an off white solid; Rt 1.91 min; m/z 533 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.78-7.67 (m, 2H), 7.62 (dd, J=1.7, 0.6 Hz, 1H),7.28-7.15 (m, 2H), 7.07 (d, J=9.1 Hz, 1H), 5.91 (dd, J=8.2, 2.3 Hz, 1H),5.76 (s, 1H), 5.09 (p, J=8.9 Hz, 1H), 4.83-4.73 (m, 2H), 4.70 (s, 2H),3.78 (s, 3H), 3.03 (t, J=10.1 Hz, 2H), 2.91-2.51 (m, 3H), 2.51-2.45 (m,1H), 2.37 (s, 3H), 2.20 (s, 3H), 2.15-2.05 (m, 1H).

Example 123:(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (17.75 mg, 0.038 mmol) was added to a solution of DBU (40.3 μl,0.268 mmol), Intermediate E16 (100 mg, 0.255 mmol) and(3-fluoro-4-methoxyphenyl)boronic acid (47.6 mg, 0.280 mmol) inacetonitrile (4 mL) with stirring for 18 h at 40° C. The mixture wasconcentrated under reduced pressure. The residue was taken up in theminimum of DCM, passed through a syringe filter and the solution thenpurified by chromatography on the Companion (12 g column, 0-10% MeOH inDCM, gradient elution) to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(43 mg, 32%) as an off white solid; Rt 1.84 min; m/z 517 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.70 (dd, J=8.5, 0.7 Hz, 1H), 7.63-7.52 (m, 2H),7.18 (dd, J=8.4, 1.7 Hz, 1H), 7.07 (dd, J=4.6, 2.0 Hz, 2H), 5.87 (dd,J=8.2, 2.2 Hz, 1H), 5.08 (p, J=8.9 Hz, 1H), 4.82-4.73 (m, 2H), 4.69 (s,2H), 3.75 (s, 3H), 3.03 (q, J=9.8 Hz, 2H), 2.92-2.51 (m, 4H), 2.36 (s,3H), 2.19 (s, 3H), 2.12-2.00 (m, 1H), 1.70-1.58 (m, 1H).

Example 141:(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone

A stirred solution of DMSO (101 μL, 1.418 mmol) in DCM (1703 μL, 26.5mmol) at −78° C. was treated with oxalyl chloride dropwise (124 μL,1.418 mmol). After 15 min at −78° C., a solution of(1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol(300 mg, 0.945 mmol) in DCM (1 mL) was slowly added. After 45 min at−78° C., DIPEA (826 μl, 4.73 mmol) was slowly added. The reactionmixture was stirred at −70° C. for 20 h, then quenched with NaHCO₃ (20mL) and diluted in DCM (10 mL) then split by passing through aPhaseSep©, washing with further DCM. The solution was concentrated invacuo to give an orange red crude solid (0.378 g), which was purified byflash chromatography on the Companion (12 g, DCM/AcOEt: 100/0 to 90/10)to afford(R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone(0.264 g, 86%) as a sticky orange oil; Rt 2.00 min; m/z 316 (M+H)+(ES+).

(R)—N-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

DAST (3.51 ml, 9.51 mmol) was added dropwise to stirred, cooled (0° C.)solution of(R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone(1.0 g, 3.17 mmol) in DCE (9.99 ml, 127 mmol). The reaction was stirredat RT over the week end then for another 20 h. The reaction was quenchedinto saturated aqueous NaHCO₃ solution (100 mL) (gas evolution), thephases separated, the aqueous extracted with DCM (3×150 mL), thecombined organics were dried on MgSO₄ and filtered through a PhaseSep©and concentrated in vacuo to give a dark brown crude oil which waspurified by chromatography column (24 g, DCM 100%) to give(R)—N-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(0.87 g, 80%) was isolated as a red oil; Rt 2.44 min; m/z 338 (M+H)+(ES+).

(R)—N¹-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine

Sodium dithionite (5.52 g, 26.8 mmol) was added to a mixture(R)—N-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline(0.903 g, 2.68 mmol), concentrated ammonia (2.085 ml, 53.5 mmol), water(8.10 ml, 450 mmol) and THF (10.09 ml, 123 mmol) then stirred at roomtemperature overnight. After 15 h of stirring, the reaction mixture wasfiltered to remove the white solid. The solid was washed with AcOEt (100mL). The layers were separated then the aqueous extracted with EtOAc(2×100 mL), the combined organics washed with water (50 mL) and brine(50 mL), dried (MgSO₄), filtered and evaporated in vacuo to give a crudematerial as a brown solid, which was dissolved in AcOEt (50 mL), washedwith aqueous NaOH (1M; 10 mL) and brine (20 mL). The organic layer wasdried (MgSO₄), filtered and concentrated to give a beige foam, which Thefoam was dissolved in DCM and loaded on SCX. Capture (washing usingMeOH) and release using 1% NH3 in MeOH afforded(R)—N¹-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(0.685 g, 79%) was isolated as a brown glass; Rt 1.88 min; m/z 308(M+H)+ (ES+).

(S)—N-(2-(((R)-3,3-difluorocyclopentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide

DIPEA (0.973 ml, 5.57 mmol) was added to a solution of(R)—N¹-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(0.685 g, 2.229 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.317 g,2.452 mmol) and HATU (1.102 g, 2.90 mmol) in DMF (7.42 mL, 96 mmol). Thebrown solution was stirred at RT for 15 h, then diluted with DCM (100mL) and washed with sodium bicarbonate saturated aqueous solution (100mL). The aqueous extracts were extracted with DCM (2×100 mL) and theorganics were combined and washed with brine (100 ml), dried (MgSO₄),filtered and concentrated in vacuo to give a crude mixture. The crudewas dried on silica and purified by chromatography column (24 g,DCM/AcOEt: 100/0 to 100/100) to give(S)—N-(2-(((R)-3,3-difluorocyclopentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(0.7 g, 72%) was isolated as an off white solid; Rt 1.78 min; m/z 419(M+H)+ (ES+).

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(S)—N-(2-(((R)-3,3-difluorocyclopentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (0.7 g, 1.673 mmol) was dissolved in aceticacid (6.70 mL, 117 mmol) and stirred at 70° C. for 15 h. The reactionwas cooled down to r.t. and stored in the cold room over the week-endand the reaction was concentrated in vacuo. The crude brown oil waspurified by flash chromatography (12 g, DCM/MeOH: 100/0 to 90/10) thenby capture and release on SCX resin to afford a brown oil (530 mg),which was purified by chromatography column (12 g, AcOEt/MeOH: 100/0 to95/5) to afford(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(0.267 g, 38%) was isolated as a white solid; Rt 1.65 min; m/z 401(M+H)+ (ES+).

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.125 mmol) in pyridine (1.50 mL, 18.61 mmol) then the mixturewas stirred for 15 min at 40° C. (3,4-difluorophenyl)boronic acid (52.3mg, 0.331 mmol) was added then the mixture was heated to 40° C. for 2 h.The reaction was cooled down to RT and stirred overnight at the sametemperature. The mixture was diluted with ethyl acetate (20 mL) thenwashed with water (3×10 mL). The organic phase was then filtered througha phase sep cartridge and concentrated under reduced pressure. Theresidue was taken up in DCM purified by chromatography on the Companion(4 g column, 0-10% (10% MeOH in DCM) in DCM, gradient elution). Afterconcentration of the combined fractions, diethyl ether (10 mL) was addedand the suspension was concentrated in vacuo to afford((S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (51 mg, 78%) as a white foam; Rt 2.33 min; m/z513 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.89-7.79 (m, 1H), 7.67-7.59 (m,2H), 7.42-7.32 (m, 1H), 7.28-7.17 (m, 2H), 6.09 (td, J=8.2 Hz, 1H), 5.39(p, J=9.1 Hz, 1H), 2.88-2.44 (m, 7H), 2.36 (s, 3H), 2.34-2.22 (m, 2H),2.20 (s, 3H), 2.16-2.01 (m, 1H).

Example 142:(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.125 mmol) in pyridine (1.505 mL, 18.61 mmol) then the mixturewas stirred for 15 min at 40° C. (3-fluoro-4-methoxyphenyl)boronic acid(56.2 mg, 0.331 mmol) was added then the mixture was heated to 40° C.for 2 h. The mixture was diluted with ethyl acetate (20 mL) then washedwith water (3×10 mL). The organic phase was then filtered through aphase sep cartridge and concentrated under reduced pressure. The residuewas taken up in DCM purified by chromatography on the Companion (4 gcolumn, 0-10% (10% MeOH in DCM) in DCM, gradient elution). Afterconcentration of the combined fractions, diethyl ether (10 mL) was addedand the suspension was concentrated in vacuo to afford(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (53 mg, 79%) as a yellowish foam; Rt 2.21 min;m/z 525 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.66-7.64 (m, 1H), 7.64-7.58(m, 2H), 7.24 (dt, J=8.5, 1.9 Hz, 1H), 7.14-7.02 (m, 2H), 6.03 (td,J=7.6 Hz, 1H), 5.46-5.32 (m, 1H), 3.75 (s, 3H), 2.82-2.42 (m, 7H), 2.37(s, 3H), 2.34-2.22 (m, 2H), 2.20 (s, 3H), 2.15-2.07 (m, 1H).

Example 143:(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.125 mmol) in pyridine (1.50 mL, 18.61 mmol) then the mixturewas stirred for 15 min at 40° C. (3-Chloro-4-methoxyphenyl)boronic acid(61.7 mg, 0.331 mmol) was added then the mixture was heated to 40° C.for 2 h. The reaction was cooled down to RT and the mixture was dilutedwith ethyl acetate (20 mL) then washed with water (3×10 mL). The organicphase was then filtered through a PhaseSep cartridge and concentratedunder reduced pressure. The residue was taken up in DCM purified bychromatography on the Companion (4 g column, 0-10% (10% MeOH in DCM) inDCM, gradient elution). After concentration of the combined fractions,diethyl ether (10 mL) was added and the suspension was concentrated invacuo to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(52 mg, 75%) as a white foam; Rt 2.28 min; m/z 541 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.79 (dd, J=3.9, 2.6 Hz, 1H), 7.65 (d, 1H), 7.61 (t, J=8.4Hz, 1H), 7.33-7.21 (m, 2H), 7.07 (dd, J=9.1, 2.9 Hz, 1H), 6.06 (td,J=8.6 Hz, 1H), 5.42 (q, J=9.2 Hz, 1H), 3.77 (s, 3H), 2.82-2.40 (m, 7H),2.37 (s, 3H), 2.34-2.22 (m, 2H), 2.20 (s, 3H), 2.18-2.07 (m, 1H).

Example 144:(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneand Example 145:(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-hydroxypropyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

TEA (2.88 mL, 20.66 mmol) was added to a solution of Intermediate C19(1.8 g, 6.89 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.978 g,7.58 mmol) and HATU (2.88 g, 7.58 mmol) in DMF (15 ml, 194 mmol) thenstirred at RT for 6 hrs. The bulk of the DMF was removed under vacuum.The loose residue was diluted with water (10 mL) then extracted with DCM(50 mL). The organic phase was washed with water (10 ml) then passedthrough a phase sep cartridge and concentrated in vacuo. The residue waspurified by chromatography (24 g silica, 0-10% methanol in DCM, gradientelution) to afford(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-hydroxypropyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(1.94 g, 68%) as a tan solid; Rt 0.79 min; m/z 373 (M+H)+ (ES+).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(2 Single Diastereoisomers, Alcohol Stereochemistry Unknown)

(2S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-hydroxypropyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(1.94 g, 5.21 mmol) was heated to 80° C. in acetic acid (11.93 mL, 208mmol) for 3 h. The reaction mixture was concentrated. The crude productwas purified by flash chromatography (40 g column, 0-10% (0.7 MAmmonia/MeOH)/DCM) to afford(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneDiastereoisomer 1 (666 mg, 36%) and(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one Diastereoisomer 2 (671mg, 34% yield) as tan solids (absolute stereochemistry of alcoholunknown).

Diastereoisomer 1: Rt 0.74 min; m/z 355 (M+H)+ (ES+); Diastereoisomer 2Rt 0.68 min; m/z 355 (M+H)+ (ES+).

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Diastereoisomer 1)

DBU (0.085 ml, 0.564 mmol) was added to a solution of(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneDiastereoisomer 1 (100 mg, 0.282 mmol) in MeCN (2.5 ml, 47.9 mmol), DCM(0.25 ml, 3.89 mmol) and the mixture was stirred for 10 min. CuTMEDA(13.10 mg, 0.028 mmol) was added, stirred for a 10 min,(3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) added and thereaction stirred at 35° C. for 20 h. Additional(3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) and(3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) were added andthe mixture was stirred for a further 5 h. The mixture was concentratedonto loose silica gel. The silicate was purified by chromatography onthe Companion (12 g column, 0-4% MeOH/DCM) to afford(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Diastereoisomer 1) (40 mg, 30%) as an off white solid; Rt 1.82 min; m/z467 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.86 (1H, ddd, J=13.6, 7.4, 2.7Hz), 7.68 (1H, d, J=8.3 Hz), 7.57 (1H, d, J=1.5 Hz), 7.49 (1H, d, J=8.9Hz), 7.37-7.23 (1H, m), 7.20 (1H, dd, J=8.4, 1.6 Hz), 5.95 (1H, d, J=7.0Hz), 5.28 (1H, d, J=4.1 Hz), 4.46-4.27 (1H, m), 4.17-3.98 (2H, m),2.75-2.56 (3H, m), 2.57-2.53 (1H, m), 2.36 (3H, s), 2.19 (3H, s), 1.29(3H, d, J=5.5 Hz). Chiral HPLC (Diacel Chiralpak IA, 5 um, 4.6×250 mm,30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA):RT=6.95 min, >99% de @ 254 nm.

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Diastereoisomer 2)

DBU (0.085 mL, 0.564 mmol) was added to a solution of(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneDiastereoisomer 2 (100 mg, 0.282 mmol) in MeCN (2.5 ml, 47.9 mmol), DCM(0.25 mL, 3.89 mmol) and the mixture was stirred for 10 min. CuTMEDA(13.10 mg, 0.028 mmol) was added, the mixture was stirred for a 10 min,(3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) added and thereaction stirred at 35° C. for 20 h. Additional CuTMEDA (13.10 mg, 0.028mmol) and (3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) wereadded and the mixture was stirred for a further 5 h. The mixture wasconcentrated onto loose silica gel. The silicate was purified by flashchromatography on the Companion (12 g column, 0-4% MeOH/DCM then 4 gcolumn, 100% EtOAc) to afford(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Diastereoisomer 2) (22 mg, 16%) as a colourless solid; Rt 1.81 min; m/z467 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.78 (1H, ddd, J=13.2, 7.4, 2.5Hz), 7.66 (1H, dd, J=8.4, 0.7 Hz), 7.59 (1H, dd, J=1.6, 0.6 Hz),7.41-7.22 (2H, m), 7.19 (1H, dd, J=8.3, 1.6 Hz), 5.96 (1H, dd, J=8.2,2.2 Hz), 5.20 (1H, d, J=4.5 Hz), 4.35-4.21 (2H, m), 4.13-3.97 (1H, m),2.83-2.72 (1H, m), 2.63-2.51 (2H, m), 2.36 (3H, s), 2.28-2.20 (1H, m),2.19 (3H, s), 1.22 (3H, d, J=6.3 Hz); Chiral HPLC (Lab 1 Bay 4, DiacelChiralpak IA, 5 urn, 4.6×250 mm, 30 min method, 1.0 ml/min, isocratic30% EtOH in isohexane (0.2% TFA): RT=6.39 min, >99% de @ 254 nm.

General Route B: Convergent Approach to γ-Lactam Analogues fromN-Arylpyroglutamic Acid Ex 109(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one4-(3,5-Dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline

4-(3,5-dimethylisoxazol-4-yl)-N-trans-((1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline(0.417 g, 1.159 mmol, 73.6% yield) is dissolved in dry THF (9.94 ml, 121mmol). This solution is cooled to 0° C., then 18-CROWN-6 (0.458 g, 1.733mmol) in dry THF (9.94 ml, 121 mmol) was added followed with NaH (0.069g, 1.733 mmol). After 15 mn of stirring, ETHYL IODIDE (0.140 ml, 1.733mmol) is added. The reaction was stirred overnight at RT then saturatedammonium chloride (10 mL) was added, followed by DCM (2×5 mL) themixture is shaken in a separating funnel. The organic layer was thenfiltered through a PhaseSep© cartridge then concentrated to give anorange oil, which was purified by flash chromatography (24 g, DCM/MeOH:100/0 to 95/5) to afford4-(3,5-dimethylisoxazol-4-yl)-N-trans-((1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline(0.417 g, 74% yield) was isolated as an orange oil; Rt 2.58 min (method1), m/z 346 (M+H)+ (ES+).

4-(3,5-dimethylisoxazol-4-yl)-N¹-(trans-(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine

4-(3,5-Dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline(0.417 g, 1.207 mmol) and concentrated ammonia (0.752 ml, 19.32 mmol)were dissolved in THF/water (1:1, 23 mL) then sodium dithionite (2.488g, 12.07 mmol) was added and the reaction mixture stirred at RT for 18hours. The layers were separated, the aqueous further extracted withEtOAc (2×100 mL). The combined organics were washed with water (50 mL)and brine (50 mL), dried (MgSO₄), filtered and evaporated in vacuo togive4-(3,5-dimethylisoxazol-4-yl)-N¹-(trans-(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine(0.31 g, 80%) as a pink solid; Rt 1.64 min (method 1), m/z 316 (M+H)+(ES+).

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid

DBU (2.4 ml, 15.92 mmol) was added to a suspension of(S)-5-oxopyrrolidine-2-carboxylic acid (1.0 g, 7.75 mmol) inacetonitrile (15 mL) then stirred for 10 minutes at room temperature.CuTMEDA (100 mg, 0.215 mmol) was added then the mixture was stirred fora further 10 minutes. (3,4-difluorophenyl)boronic acid (1.25 g, 7.92mmol) was added then the mixture was heated to 50° C. for 18 h. CuTMEDA(100 mg, 0.215 mmol) was added then the mixture was stirred for afurther 18 h (Reaction A). Subsequently, DBU (20 ml, 133 mmol) was addedto a suspension of (S)-5-oxopyrrolidine-2-carboxylic acid (8.0 g, 62.0mmol) in acetonitrile (15 mL) then stirred for 10 minutes at roomtemperature. CuTMEDA (1.5 g, 3.23 mmol) was added then the mixture wasstirred for a further 10 minutes. (3,4-difluorophenyl)boronic acid (10.0g, 63.3 mmol) was added then the mixture was heated to 50° C. for 18 h(Reaction B). The mixture of Reaction A was combined with that ofReaction B then concentrated under reduced pressure. The residue wasdiluted with water (200 mL) then extracted with diethyl ether (2×200mL). The aqueous layer was treated with 1 M aqueous hydrogen chloride(200 mL, 200 mmol) then extracted with ethyl acetate (3×200 mL). Thecombined organic phases were concentrated onto loose silica gel. Thesilicate was purified on a silica gel filter plug, eluting withEtOAc/dichloromethane (0-100%) to give after prolonged rotaryevaporation (S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylicacid (2.8 g, 16%) as a pale yellow glass; Rt 1.41 min (method 1), m/z242 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-ethoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

DIPEA (0.208 ml, 1.189 mmol) was added to a solution of4-(3,5-dimethylisoxazol-4-yl)-N1-(trans-(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine(0.15 g, 0.476 mmol),(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (0.126 g,0.523 mmol) and HATU (0.235 g, 0.618 mmol) in DMF (1.583 ml, 20.45mmol). The brown solution was stirred at RT for 3 h then the mixture waspartitioned between ethyl acetate (100 mL) and water (100 mL), then thelayers separated. The organic phase was washed with water (3×100 mL) andwith brine (100 mL), then concentrated in vacuo to give a crude brownoil (340 mg), which was purified by flash chromatography on theCompanion (4 g, 0-10% MeOH/DCM) to give(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-ethoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (0.238 g, 91%) was obtained as acolourless foam; Rt 2.24 min (method 1), m/z 539 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-ethoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (0.238 g, 0.442mmol) was dissolved in acetic acid (1.771 ml, 30.9 mmol) and stirred at70° C. for 15 h. After 15 h, the reaction was cooled down to RT andconcentrated in vacuo to give a brown oil, which was purified by flashchromatography on the Companion (4 g, DCM/MeOH: 100/0 to 90/10). Theimpure fractions containing the desired product were combined (150 mg)and purified again on a 12 g column using the same conditions then usinga different solvent system (12 g, DCM/AcOEt: 100/0 to 0/100) to give abrown solid (69 mg). Final purification by flash chromatography on theCompanion (4 g, DCM/AcOEt: 100/0 to 0/100) gave(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(14 mg, 6%) as a beige solid; Rt 2.25 min (method 1), m/z 521 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.80 (tdd, J=13.7, 7.4, 2.6 Hz, 1H),7.66-7.57 (m, 2H), 7.42-7.33 (m, 1H), 7.28-7.19 (m, 1H), 7.19-7.15 (m,1H), 6.20-6.04 (dd, 1H), 5.25-5.10 (m, 1H), 4.33-4.19 (m, 1H), 3.54-3.44(m, 2H), 2.79-2.52 (m, 3H), 2.43-2.27 (m, 5H), 2.26-2.02 (m, 7H),1.89-1.75 (m, 1H), 1.17 (t, J=7.0 Hz, 3H).

Example 116:5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one(2S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-oxopiperidin-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide(Intermediate D14)

DIPEA (288 μL, 1.649 mmol) was added to a solution of4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidin-2-one(198 mg, 0.660 mmol),(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (175 mg,0.726 mmol) and HATU (326 mg, 0.857 mmol) in DMF (2196 μL, 28.4 mmol).The green solution was stirred at RT for 15 h then partitioned betweenethyl acetate (100 mL) and water (100 mL), then the layers separated.The organic phase was further washed with brine (100 mL) andconcentrated in vacuo to give a crude oil. Purification by flashchromatography on the Companion (12 g, 0-10% MeOH/DCM) to afford(2S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-oxopiperidin-4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamideIntermediate D14 (0.356 g, 93%) as a colorless oil; Rt 1.68 min (method1), m/z 524 (M+H)+ (ES+).

5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one

Intermediate D14 (0.191 g, 0.317 mmol) was dissolved in acetic acid(1.27 mL, 22.22 mmol) and heated at 90° C. The reaction was concentratedin vacuo and TFA (1.71 mL, 22.22 mmol) was added. The mixture was heatedat 70° C. for 15 h, the mixture was cooled down to RT and concentratedin vacuo/pre-adsorbed on silica gel. Flash chromatography on theCompanion (4 g, DCM/MeOH: 100/0 to 90/10) gave5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one (31 mg, 19%) as a pink solid; Rt 1.64 min (method 1),m/z 506 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.92 (d, J=8.5 Hz, 1H), 7.83(ddd, 1H), 7.80-7.75 (m, 1H), 7.64-7.58 (m, 1H), 7.36 (dt, J=10.5, 9.1Hz, 1H), 7.26-7.20 (m, 1H), 7.17 (dd, J=8.5, 1.7 Hz, 1H), 6.15 (d, J=7.4Hz, 1H), 5.06-4.95 (m, 1H), 3.91 (t, J=11.1 Hz, 1H), 3.44-3.35 (m, 1H),2.90-2.73 (m, 1H), 2.73-2.62 (m, 1H), 2.62-2.49 (m, 1H), 2.48-2.38 (m,1H), 2.36 (s, 3H), 2.19 (s, 3H), 2.13-1.98 (m, 2H).

Example 117:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

Intermediate D14 (356 mg, 0.612 mmol) was dissolved in acetic acid(2.725 mL, 47.6 mmol) and heated at 90° C. for 4 h. The reaction wasconcentrated in vacuo and TFA (3.67 mL, 47.6 mmol) was added. Themixture was heated at 70° C. for 15 h, then cooled down to RT andconcentrated in vacuo. The resulting black oil was purified by flashchromatography on the Companion (4 g, DCM/MeOH: 100/0 to 90/10) toafford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(112 mg, 39%) was isolated as a beige solid; Rt 1.70 min (method 1), m/z409 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.79 (ddd, J=13.1, 7.4, 2.6 Hz,1H), 7.62 (dd, J=8.3, 0.7 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.44-7.32 (m,1H), 7.29-7.25 (m, 1H), 7.19 (dd, J=8.3, 1.6 Hz, 1H), 5.74 (d, 1H),2.85-2.75 (m, 1H), 2.73-2.62 (m, 1H), 2.61-2.48 (m, 1H), 2.37 (s, 3H),2.23-2.14 (m+s, 4H).

Example 124:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneand Example 125:(1S,3r)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclobutylacetate(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide

TEA (765 μL, 5.49 mmol) was added to a solution of Intermediate C17 (500mg, 1.829 mmol),(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (485 mg,2.012 mmol) and HATU (765 mg, 2.012 mmol) in DMF (5 mL) then stirred atRT for 48 h. The bulk of the DMF was removed under vacuum. The looseresidue was diluted with water (10 mL) then extracted with DCM (30 mL).The organic phase was washed with water (10 ml) then passed through aphase sep cartridge and concentrated in vacuo. The residue was purifiedby chromatography (24 g silica, 0-10% methanol in DCM, gradient elution)to afford(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (500 mg, 55%) as a pale brownsolid; Rt 1.79 min; m/z 497 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (100 mg, 0.201 mmol) wasdissolved in acetic acid (1 mL) and stirred at 80° C. for 18 h. Thereaction mixture was cooled to RT and the solvent was removed in vacuo.The residue was purified by chromatography (12 g silica, 0-10% methanolin DCM, gradient elution). Product fractions were combined andconcentrated in vacuo to afford((S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(41 mg, 41%) as a light beige solid; Rt 1.79 min (method 1), m/z 479(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.86-7.74 (m, 2H), 7.60 (d, J=1.6 Hz,1H), 7.43-7.30 (m, 1H), 7.20 (dt, J=9.1, 2.0 Hz, 2H), 6.04-5.96 (m, 1H),5.49 (p, J=8.6 Hz, 1H), 5.37 (d, J=3.9 Hz, 1H), 4.61 (s, 1H), 3.08 (dtd,J=36.6, 15.0, 14.1, 6.5 Hz, 2H), 2.74-2.52 (m, 3H), 2.46 (m, 1H), 2.36(s, 3H), 2.19 (s, 3H), 2.11-1.96 (m, 2H).

Fractions containing the acetate were combined and concentrated in vacuoto afford(1S,3r)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclobutylacetate (27 mg, 24%) as a; Rt 2.11 min (method 1), m/z 521 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.92 (d, J=8.4 Hz, 1H), 7.83 (ddd, J=13.2, 7.5, 2.7Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.37 (dt, J=10.6, 9.1 Hz, 1H), 7.22(dd, J=8.5, 1.7 Hz, 2H), 6.03 (d, J=7.1 Hz, 1H), 5.51 (p, J=8.7 Hz, 1H),5.34 (t, J=7.3 Hz, 1H), 3.44-3.14 (m, 3H), 2.76-2.51 (m, 4H), 2.37 (s,3H), 2.20 (s, 3H), 2.13 (s, 3H), 2.07 (m, 1H).

General Route C: Reductive Amination Approach to γ-Lactam AnaloguesExample 126:(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

A mixture of potassium carbonate (14.33 g, 104 mmol),(3,5-dimethylisoxazol-4-yl)boronic acid (7.31 g, 51.8 mmol) and5-bromo-2-nitroaniline (7.5 g, 34.6 mmol) in 1,4-dioxane:water (4:1, 150mL) was evacuated then backfilled with nitrogen three times. PdCl₂(dppf)(1.770 g, 2.419 mmol) was added then the mixture was heated to 90° C.under nitrogen for 16 hrs. The reaction mixture was cooled to rt thendiluted with water (50 mL) and extracted with ethyl acetate (2×45 mL).Combined organics were dried (MgSO₄), filtered and evaporated underreduced pressure. The crude product was dissolved in DCM and passedthrough a plug of silica (˜2 cm thick) to afford a yellow solid, whichwas triturated with Et₂O (2×100 mL). The resultant solid was filtered,rinsing with Et₂O (50 mL), and dried in vacuo to afford5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (6.64 g, 79%) as a yellowsolid; Rt 1.88 min (method 1), m/z 234 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carbonyl chloride

To a suspension of(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (1.45 g, 6mmol) in anhydrous THF (5 mL, 61.0 mmol) cooled to 0° C., thionylchloride (0.482 mL, 6.60 mmol) was added dropwise. The resultingsolution was stirred for 6 h at room temperature and the solvent wasevaporated under vacuum to give the crude(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carbonyl chloride (1.6 g,51%) which was used without further purification.

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carbonyl chloride (779 mg,3 mmol) in DCM (7 mL, 109 mmol) was added to a solution of5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (636 mg, 2.73 mmol) in DCM(7 mL, 109 mmol) at 0° C. then stirred at room temperature for 18 hours.The mixture was diluted with water (20 mL) then extracted with ethylacetate (3×30 mL). The combined organic phases were washed with 1M HCl(10 mL), saturated aqueous NaHCO3 (10 mL) and saturated brine (10 mL),then dried (MgSO₄), filtered and concentrated to give a brown oil. Thecrude product was purified by flash chromatography (40 g column, 0-100%EtOAc/isohexane) to afford(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide(425 mg, 32%) as a yellow solid; Rt 1.13 min (method 1), m/z 427 (M+H)+(ES+).

(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

A suspension of(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide(420 mg, 0.920 mmol) and 5% Pt/Al2O3-5R94 (42 mg, 10.76 μmol) in ethanol(25 ml, 428 mmol) was stirred under 2 bar of hydrogen at roomtemperature for 24 h. The white suspension was diluted with THF (10 mL)and then filtered through Celite©, washing with ethanol (50 mL) and THF(20 mL) and the solvent was removed under reduced pressure. Theresulting yellow solid was dissolved in ethanol (25 mL, 428 mmol) andTHF (5 mL) and 5% Pt/Al2O3-5R94 (42 mg, 10.76 μmol) was added and thereaction mixture was stirred under 2 bar of hydrogen at room temperaturefor a further 3 h. The reaction mixture was filtered through Celite©,washing with Ethanol (50 mL) and THF (20 mL) and the solvent was removedunder reduced pressure to give(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(386 mg, 89%) a yellow solid; Rt 1.13 min (method 1), m/z 427 (M+H)+(ES+).

(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(30 mg, 0.070 mmol) and DCM (1 mL, 15.54 mmol) were added benzaldehyde(9.30 μL, 0.091 mmol) and acetic acid (0.5 mL, 8.73 mmol). The mixturewas stirred at room temperature for 20 minutes then pyridine borane(0.015 mL, 0.141 mmol) was added. The mixture was stirred at roomtemperature for 1 hour, then a few drops of concentrated HCl were addedand the mixture was stirred at 80° C. for 1 hour. Additional acetic acid(0.5 mL, 8.73 mmol) was added and stirred at RT overnight. The mixturewas concentrated under reduced pressure. The crude product was purifiedby chromatography on silica gel (12 g column, 0-5% MeOH/DCM) to afford((S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(15 mg, 41%) as a tanned solid; Rt 2.26 min (method 1), m/z 499 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.69-7.57 (m, 3H), 7.41-7.30 (m, 3H),7.31-7.16 (m, 4H), 7.10-6.97 (m, 1H), 5.95-5.83 (m, 1H), 5.73 (d, J=16.6Hz, 1H), 5.63 (d, J=16.6 Hz, 1H), 2.80-2.66 (m, 2H), 2.49-2.42 (m, 1H),2.38 (s, 3H), 2.21 (s, 3H), 1.90-1.79 (m, 1H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30%EtOH in isohexane (0.2% TFA): 156281, RT=5.65 min, >99% ee @ 254 nm.

Example 127:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(50 mg, 0.117 mmol) in THF (2 mL, 24.41 mmol) was added propionaldehyde(11.00 μL, 0.152 mmol) and stirred at RT for 1 h. Then sodiumtriacetoxyborohydride (39.8 mg, 0.188 mmol) was added and stirred at RTfor 4 h. Additional propionaldehyde (3 μL) was added and the mixture wasstirred for a further 3 h. The reaction mixture was diluted with MeOHand loaded onto a column of SCX (2 g) in MeOH. The column was washedwith MeOH and then the product was eluted with 0.7 M ammonia in MeOH.The resultant mixture was concentrated in vacuo to afford Product IV asa yellow residue (82 mg). The yellow residue was heated to 80° C. inacetic acid (2 mL, 34.9 mmol) for 18 h. The reaction mixture wasconcentrated and the crude product was purified by preparative HPLC(Acquity, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 35-65% MeCN in Water) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(10 mg, 18%) as a tan solid; Rt 2.10 min (method 1), m/z 451 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.76 (1H, ddd, J=13.0, 7.4, 2.6 Hz),7.71-7.64 (1H, m), 7.59 (1H, dd, J=1.6, 0.6 Hz), 7.37 (1H, dt, J=10.6,9.1 Hz), 7.24-7.14 (2H, m), 6.03-5.95 (1H, m), 4.35 (1H, dt, J=14.8, 7.4Hz), 4.25 (1H, dt, J=14.8, 7.6 Hz), 2.88-2.73 (1H, m), 2.70-2.52 (2H,m), 2.36 (3H, s), 2.19 (3H, s), 2.08 (1H, t, J=10.6 Hz), 1.78 (2H, q,J=7.4 Hz), 0.95 (3H, t, J=7.4 Hz).

Example 128:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(100 mg, 0.235 mmol) and isobutyraldehyde (0.025 mL, 0.469 mmol) in THF(2 mL, 24.41 mmol) at rt was added acetic acid (0.013 mL, 0.235 mmol)and was stirred at RT for 1 h. Then sodium triacetoxyborohydride (80 mg,0.375 mmol) was added and stirred at RT for 4 h. The reaction mixturewas diluted with MeOH and loaded onto a column of SCX (2 g) in MeOH. Thecolumn was washed with MeOH and then the product was eluted with 0.7 Mammonia in MeOH. The resultant mixture was concentrated in vacuo toafford a yellow residue, which was heated to 80° C. in acetic acid (2mL, 34.9 mmol) for 18 h. The reaction mixture was concentrated and thecrude product was purified by preparative HPLC (Acquity, Acidic (0.1%Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-65%MeCN in Water) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(10 mg, 9%) as a tan solid; Rt 2.21 min (method 1), m/z 465 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.76-7.65 (m, 2H), 7.61 (d, J=1.6 Hz, 1H),7.44-7.30 (m, 1H), 7.24-7.14 (m, 2H), 5.99-5.92 (m, 1H), 4.24 (dd,J=14.6, 7.2 Hz, 1H), 4.08 (dd, J=14.5, 8.2 Hz, 1H), 2.80 (dd, J=16.5,9.0 Hz, 1H), 2.70-2.53 (m, 2H), 2.38 (s, 3H), 2.33 (p, J=1.9 Hz, 1H),2.21 (s, 3H), 2.13-2.05 (m, 1H), 0.96 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6Hz, 3H); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=13.2min, >99% ee @ 254 nm.

Example 129:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(100 mg, 0.235 mmol) in THF (2 mL, 24.41 mmol) was added3-methoxypropanal (31.0 mg, 0.352 mmol) and stirred at RT for 1 h. Thensodium triacetoxyborohydride (80 mg, 0.375 mmol) was added and stirredat RT for 4 h. The reaction mixture was diluted with MeOH and loadedonto a column of SCX (2 g) in MeOH. The column was washed with MeOH andthen the product was eluted with 0.7 M ammonia in MeOH. The resultantmixture was concentrated in vacuo to afford a yellow residue (82 mg),which was heated to 80° C. in acetic acid (2 mL, 34.9 mmol) for 18 h.The reaction mixture was concentrated and the crude product was purifiedby preparative HPLC (Acquity, Acidic (0.1% Formic acid), Waters X-SelectPrep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (8 mg, 7%) as a tansolid; Rt 2.00 min (method 1), m/z 481 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ:7.76 (ddd, J=13.2, 7.4, 2.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.42-7.31 (m,1H), 7.27-7.14 (m, 1H), 5.93 (dd, J=8.4, 2.0 Hz, 1H), 4.44 (dt, J=14.5,7.2 Hz, 1H), 4.33 (dt, J=14.9, 7.4 Hz, 1H), 3.39 (t, J=6.0 Hz, 2H), 3.26(s, 3H), 2.82-2.53 (m, 3H), 2.37 (s, 3H), 2.35-2.31 (m, 1H), 2.20 (s,3H), 2.16-2.08 (m, 1H), 2.02 (t, J=6.6 Hz, 2H); Chiral HPLC (DiacelChiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 ml/min, isocratic 30%EtOH in isohexane (0.2% TFA): RT=7.65 min, >99% ee @ 254 nm.

Example 130:(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide

(S)-5-oxopyrrolidine-2-carbonyl chloride (0.940 g, 6.37 mmol) in DCM (7mL, 109 mmol) was added to a solution of5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (1.35 g, 5.79 mmol) in DCM(7 mL, 109 mmol) at 0° C. then stirred at room temperature overnight.The mixture was diluted with water (20 mL) then extracted with ethylacetate (3×30 mL). The combined organic phases were washed with aqueous1M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated brine (10mL), then dried (MgSO₄), filtered and concentrated to give a brown oil,which was purified by chromatography on silica gel (40 g column, 0-100%EtOAc/isohexane) to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide (1.25 g, 62%) as a yellow solid; Rt 1.53 min(method 1), m/z 345 (M+H)+ (ES+).

(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide

A suspension of(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide(550 mg, 1.597 mmol) and 5% Pt/Al₂O₃— 5R94 (55 mg, 0.014 mmol) inethanol (30 mL, 514 mmol) was stirred under 2 bar of hydrogen at roomtemperature for 20 h. The reaction mixture was filtered through Celite©,washing with ethanol (50 mL) and the solvent was removed under reducedpressure to give(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(540 mg, 100% yield) as a yellow solid; Rt 1.14 min (method 1), m/z 315(M+H)+ (ES+).

(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

4,4-difluorocyclohexanecarbaldehyde (70.5 mg, 0.476 mmol) was added to asolution of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(125 mg, 0.366 mmol) in DCM (4 mL, 62.2 mmol) at RT and stirred for 20mins. Then acetic acid (2 mL, 34.9 mmol) was added and stirred at RT fora further 20 mins then pyridine borane (0.078 mL, 0.732 mmol) was added.The reaction mixture was stirred at room temperature for 1 h then a fewdrops of concentrated HCl were added and the mixture was stirred at 80°C. for 2 h. The mixture was concentrated under reduced pressure. Thecrude product was purified by chromatography on silica gel (12 g column,0-5% (0.7 M Ammonia/MeOH)/DCM) to afford(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(45 mg, 27%) as a yellow solid; Rt 1.70 min (method 1), m/z 429 (M+H)+(ES+).

(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

DBU (0.024 ml, 0.158 mmol) was added to a solution of(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(45 mg, 0.105 mmol) in MeCN (1.5 mL, 28.7 mmol), and stirred at RT for10 min. CuTMEDA (9.76 mg, 0.021 mmol) was added, sonicated and stirredfor a further 10 min. Then (3,4-difluorophenyl)boronic acid (24.88 mg,0.158 mmol) was added and the reaction stirred at 35° C. for 24 hr. Themixture was concentrated under reduced pressure then the crude productwas purified by chromatography on silica gel (12 g column, 0-10%MeOH/DCM) to afford(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(28 mg, 49%) as a tan solid; Rt 2.30 min (method 1), m/z 541 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.76-7.64 (2H, m), 7.61 (1H, d, J=1.5 Hz),7.38 (1H, dt, J=10.7, 9.1 Hz), 7.28-7.08 (2H, m), 5.96 (1H, dd, J=8.3,2.0 Hz), 4.33 (1H, dd, J=14.6, 7.2 Hz), 4.19 (1H, dd, J=14.7, 8.0 Hz),2.88-2.75 (1H, m), 2.71-2.51 (2H, m), 2.37 (3H, s), 2.20 (3H, s),2.06-1.91 (4H, m), 1.85-1.61 (3H, m), 1.56-1.33 (3H, m); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): 156287, RT=6.65 min, >99% ee@ 254 nm.

Example 131:(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(50 mg, 0.146 mmol) in DCM (2 mL, 31.1 mmol) were added benzaldehyde(0.019 ml, 0.190 mmol) and acetic acid (1 mL, 17.47 mmol). The mixturewas stirred at room temperature for 20 minutes then pyridine borane(0.031 mL, 0.293 mmol) was added. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with MeOH (2mL) and loaded onto a column of SCX (1.5 g). The column was washed withMeOH and then the product was eluted with 7 M ammonia in MeOH. Theresultant mixture was concentrated in vacuo a yellow oil, which wasdissolved in acetic acid (1 mL, 17.47 mmol) and was heated to 80° C. for1 h. The crude product was loaded onto a column of SCX (1 g) in MeOH.The column was washed with MeOH and then the product was eluted with 7 Mammonia in MeOH. The resultant mixture was concentrated in vacuo toafford crude product as a pink solid. The crude product was purified byflash chromatography on silica gel (4 g column, 0-8% (0.7 MAmmonia/MeOH)/DCM) to afford(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(22 mg, 35%) as a colourless solid at 90% purity.

(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

DBU (0.012 ml, 0.077 mmol) was added to a solution of(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(22 mg, 0.051 mmol) in MeCN (1.5 ml, 28.7 mmol), and stirred for 10 minat rt. CuTMEDA (4.76 mg, 10.25 μmol) was added, sonicated and stirredfor a further 10 min. Then (3-fluoro-4-methoxyphenyl)boronic acid (13.06mg, 0.077 mmol) was added and the reaction stirred at 35° C. for 24 hr.The mixture was concentrated under reduced pressure then the crudeproduct was purified by chromatography on silica gel (12 g column, 0-10%MeOH/DCM) to afford(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(10 mg, 37%) as a colourless solid; Rt 2.14 min (method 1), m/z 511(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.64 (1H, dd, J=1.7, 0.7 Hz), 7.62(1H, dd, J=8.4, 0.7 Hz), 7.46-7.39 (1H, m), 7.38-7.28 (3H, m), 7.20 (1H,dd, J=8.3, 1.6 Hz), 7.18-7.13 (2H, m), 6.99-6.89 (2H, m), 5.88-5.81 (1H,m), 5.68 (1H, d, J=16.5 Hz), 5.61 (1H, d, J=16.5 Hz), 3.74 (3H, s),2.77-2.65 (1H, m), 2.45 (2H, dd, J=12.3, 8.1 Hz), 2.37 (3H, s), 2.20(3H, s), 1.90-1.81 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm,4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane(0.2% TFA): RT=14.1 min, 97% ee @ 254 nm.

Example 132:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(40 mg, 0.094 mmol) and DCM (1 mL, 15.54 mmol) were addednicotinaldehyde (0.011 mL, 0.122 mmol) and acetic acid (0.5 mL, 8.73mmol). The mixture was stirred at room temperature for 20 mins thenpyridine borane (0.020 mL, 0.188 mmol) was added. The mixture wasstirred at room temperature for 1 h then a few drops of concentrated HClwere added and stirring continued at RT for 5 min. Then acetic acid (1mL, 17.47 mmol) was added and the mixture was stirred at 80° C. for 18h. The mixture was concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (12 g column, 0-5%(0.7 M Ammonia/MeOH)/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(21 mg, 43%) as a colourless solid; Rt 1.66 min (method 1), m/z 500(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.58-8.47 (2H, m), 7.69-7.64 (2H, m),7.59 (1H, ddd, J=13.0, 7.4, 2.6 Hz), 7.48 (1H, dt, J=8.0, 1.9 Hz), 7.36(1H, ddd, J=7.9, 4.8, 0.9 Hz), 7.31-7.20 (2H, m), 7.12-7.03 (1H, m),5.99-5.93 (1H, m), 5.81-5.65 (2H, m), 2.80-2.68 (1H, m), 2.55-2.52 (1H,m), 2.48-2.43 (1H, m), 2.37 (3H, s), 2.20 (3H, s), 1.91-1.81 (1H, m).

Example 133:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneand Example 134:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide(125 mg, 0.366 mmol) in DCM (4 ml, 62.2 mmol) was added3-(hydroxymethyl)cyclobutanone (47.6 mg, 0.476 mmol) and ACETIC ACID (2ml, 34.9 mmol). The mixture was stirred at rt for 20 mins then PYRIDINEBORANE (0.078 ml, 0.732 mmol) was added and stirred at rt for 1 hr. Afew drops of concentrated HCl were added and the mixture was stirred at80° C. for 16 hour. The mixture was concentrated under reduced pressure.The yellow residue was dissolved in MeOH (3 ml) and K₂CO₃ (76 mg, 0.549mmol) was added and stirred at RT for 48 hrs then the mixture wasconcentrated in vacuo then partitioned between water (10 mL) and EtOAc(3×20 mL). The combined organics were washed with brine (15 mL), dried(MgSO4), and concentrated in vacuo to afford(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(150 mg, 81%) as a 1:1 mixture of diastereoisomers; Rt 1.08 min (method1), m/z 381 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3-(hydroxylmethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one and(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.083 mL, 0.549 mmol) was added to a solution of(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(139 mg, 0.366 mmol) in MeCN (8 mL, 153 mmol), and stirred for 10 min.CuTMEDA (34.0 mg, 0.073 mmol) was added, sonicated and stirred for a 10min, (3,4-difluorophenyl)boronic acid (87 mg, 0.549 mmol) added and thereaction stirred at 35° C. for 24 h. Additional DBU (0.083 mL, 0.549mmol), CuTMEDA (34.0 mg, 0.073 mmol) and (3,4-difluorophenyl)boronicacid (87 mg, 0.549 mmol) were added and the reaction mixture was stirredfor a further 18 h at 35° C. The mixture was concentrated under reducedpressure then the crude product was purified by chromatography on silicagel (24 g column, 0-5% (0.7 M Ammonia/MeOH)/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (20 mg, 11%) as ayellow solid; Rt 1.78 min (method 1), m/z 493 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 8.09 (1H, d, J=8.4 Hz), 7.79 (1H, ddd, J=13.2, 7.4, 2.6Hz), 7.59 (1H, d, J=1.6 Hz), 7.37 (1H, dt, J=10.5, 9.1 Hz), 7.23-7.15(2H, m), 6.01 (1H, dd, J=8.2, 2.1 Hz), 5.17-5.03 (1H, m), 4.97 (1H, t,J=5.1 Hz), 3.55 (2H, t, J=4.5 Hz), 2.88-2.57 (5H, m), 2.58-2.52 (1H, m),2.49-2.39 (2H, m), 2.37 (3H, s), 2.20 (3H, s), 2.14-2.01 (1H, m); ChiralHPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=4.56 min, >99% de @ 254nm.

A second fraction then gave(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1r,3S)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(15 mg, 8%) as a yellow solid; Rt 1.79 min (method 1), m/z 493 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.92 (1H, d, J=8.4 Hz), 7.77 (1H, ddd,J=13.2, 7.4, 2.6 Hz), 7.61 (1H, d, J=1.7 Hz), 7.36 (1H, dt, J=10.6, 9.2Hz), 7.26-7.15 (2H, m), 6.03-5.95 (1H, m), 5.37-5.24 (1H, m), 4.79 (1H,t, J=5.2 Hz), 3.65 (2H, dd, J=6.8, 5.1 Hz), 3.02-2.83 (2H, m), 2.77-2.51(1H, m), 2.65-2.60 (3H, m), 2.37 (2H, s), 2.36-2.30 (3H, m), 2.20 (3H,s), 2.08-1.96 (1H, m). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=4.72 min, >99% de @ 254 nm.

Example 135:(S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(50 mg, 0.117 mmol) and DCM (1 mL, 15.54 mmol) were addedcyclopropanecarbaldehyde (0.011 mL, 0.152 mmol) and acetic acid (0.5 mL,8.73 mmol). The mixture was stirred at room temperature for 20 min thenpyridine borane (0.025 ml, 0.235 mmol) was added. The mixture wasstirred at room temperature for 1 h, then a few drops of concentratedHCl were added and stirring continued at RT for 5 min. Acetic acid (0.5mL, 8.73 mmol) was added and the mixture was stirred at 80° C. for 18 h.The mixture was concentrated under reduced pressure. The crude productwas purified by flash chromatography on the Companion (12 g column, 0-5%MeOH/DCM) to afford((S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(16 mg, 29%) as a tan solid; Rt 2.11 min (method 1), m/z 463 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.76 (1H, ddd, J=13.1, 7.4, 2.6 Hz), 7.72(1H, dd, J=8.4, 0.6 Hz), 7.60 (1H, dd, J=1.6, 0.6 Hz), 7.36 (1H, dt,J=10.7, 9.1 Hz), 7.24-7.15 (2H, m), 5.97 (1H, dd, J=8.3, 1.9 Hz), 4.33(1H, dd, J=15.2, 7.0 Hz), 4.23 (1H, dd, J=15.1, 7.0 Hz), 2.80 (1H, dt,J=16.0, 9.3 Hz), 2.72-2.52 (2H, m), 2.37 (3H, s), 2.20 (3H, s), 2.09(1H, dd, J=12.9, 8.4 Hz), 1.34-1.19 (1H, m), 0.65-0.47 (4H, m).

Example 136:(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propylacetate(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propylacetate

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(40 mg, 0.094 mmol) and DCM (1 mL, 15.54 mmol) were added3-((tert-butyldimethylsilyl)oxy)propanal (0.026 ml, 0.122 mmol) andacetic acid (0.5 mL, 8.73 mmol). The mixture was stirred at roomtemperature for 20 minutes then pyridine borane (0.020 ml, 0.188 mmol)was added. The mixture was stirred at room temperature for 1 hour then afew drops of concentrated HCl were added and stirring continued at RTfor 5 min. Then acetic acid (1 mL, 17.47 mmol) was added and the mixturewas stirred at 80° C. for 18 h. The mixture was concentrated underreduced pressure. The crude product was purified by preparative HPLC(Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 35-65% MeCN in Water) to afford((S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propylacetate (4 mg, 8%) as a colourless solid; Rt 1.96 min (method 1), m/z509 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.69-7.58 (2H, m), 7.57 (1H, dd,J=1.6, 0.7 Hz), 7.28 (1H, dd, J=8.4, 1.6 Hz), 7.21 (1H, dt, J=10.2, 8.8Hz), 7.12 (1H, dddd, J=9.0, 3.9, 2.6, 1.5 Hz), 5.91 (1H, dd, J=8.4, 3.7Hz), 4.57-4.42 (2H, m), 4.20-4.06 (2H, m), 2.98 (1H, ddd, J=16.8, 9.5,7.6 Hz), 2.89-2.78 (1H, m), 2.78-2.67 (1H, m), 2.41 (3H, s), 2.37-2.27(1H, m), 2.25 (3H, s), 2.22-2.12 (2H, m), 1.90 (3H, s).

Example 137:(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(50 mg, 0.117 mmol) and DCM (1 mL, 15.54 mmol) were added tert-butyl(3-oxocyclobutyl)carbamate (21.72 mg, 0.117 mmol) and acetic acid (0.5mL, 8.73 mmol). The mixture was stirred at room temperature for 20 minthen pyridine borane (0.025 mL, 0.235 mmol) was added. The mixture wasstirred at room temperature for 1 h. A few drops of concentrated HClwere added and stirred at RT for 5 min. Then acetic acid (1 mL, 17.47mmol) was added and the mixture was stirred at 80° C. for 18 h. Themixture was concentrated under reduced pressure and the crude productwas purified by chromatography on silica gel (12 g column, 0-5%MeOH/DCM) to afford(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (29 mg, 50%) as a tan solid; Rt 1.22 min (method1), m/z 478 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: two diastereoisomers in a3:1 ratio, 8.04 (d, J=8.5 Hz, 1H, major), 7.89-7.76 (m, 2H, mixture),7.59-7.63 (m, 2H, mixture), 7.42-7.34 (m, 2H, mixture), 7.26-7.12 (m,3H, mixture), 5.99-5.91 (m, 2H, mixture), 4.82-4.69 (m, 1H, major),4.55-4.43 (m, 1H, minor), 3.31-3.19 (m, 1H, mixture), 2.89-2.76 (m, 2H,mixture), 2.77-2.60 (m, 3H, mixture), 2.59-2.52 (m, 1H, mixture), 2.37(s, 3H, mixture), 2.33-2.24 (m, 1H, mixture), 2.20 (s, 3H, mixture),2.11-2.01 (m, 1H, mixture).

Example 138:(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(75 mg, 0.176 mmol) in DCM (1.5 mL, 23.31 mmol) were addedthiazole-4-carbaldehyde (0.032 mL, 0.229 mmol) and acetic acid (0.75 mL,13.10 mmol). The mixture was stirred at room temperature for 20 minutesthen pyridine borane (0.037 mL, 0.352 mmol) was added. The mixture wasstirred at room temperature for 1 hour.

A few drops of concentrated HCl were added and stirring continued at RTfor 5 min. Then acetic acid (0.75 mL, 13.10 mmol) was added and themixture was stirred at 80° C. for 18 h. The mixture was concentratedunder reduced pressure. The crude product was purified by chromatographyon silica gel (12 g column, 0-5% MeOH/DCM) to afford(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(65 mg, 72%) as a tanned solid; Rt 2.01 min (method 1), m/z 506 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 9.14 (d, J=1.9 Hz, 1H), 7.99 (d, J=2.0 Hz,1H), 7.88 (ddd, J=13.6, 7.4, 2.6 Hz, 1H), 7.79-7.70 (m, 1H), 7.62-7.53(m, 1H), 7.49-7.39 (m, 1H), 7.34 (dt, J=10.5, 9.2 Hz, 1H), 7.20 (dd,J=8.4, 1.6 Hz, 1H), 6.18-6.10 (m, 1H), 5.80 (d, J=16.1 Hz, 1H), 5.71 (d,J=16.1 Hz, 1H), 2.80-2.57 (m, 3H), 2.35 (s, 3H), 2.18 (s, 3H), 2.15-2.09(m, 1H).

Example 139:(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

To a mixture of(S)—N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(0.094 ml, 0.176 mmol) and DCM (1.5 mL, 23.31 mmol) were added3-oxocyclobutanecarboxylic acid (26.1 mg, 0.229 mmol) and acetic acid(0.75 mL, 13.10 mmol). The mixture was stirred at room temperature for20 minutes then pyridine borane (0.037 mL, 0.352 mmol) was added. Themixture was stirred at room temperature for 1 hour. A few drops ofconcentrated HCl were added and stirring continued at RT for 5 min. Thenacetic acid (0.75 mL, 13.10 mmol) was added and the mixture was stirredat 80° C. for 18 hr. The mixture was concentrated under reducedpressure. The crude product was purified by chromatography on silica gel(12 g column, 0-5% MeOH/DCM) to afford(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclobutanecarboxylic acid (40 mg, 43%) as a tanned solid;Rt 1.91 min (method 1), m/z 507 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.45(d, J=8.5 Hz, 0.5H), 8.12 (t, J=5.7 Hz, 0.5H), 7.96 (t, J=5.7 Hz, 0.5H),7.91 (d, J=8.4 Hz, 0.5H), 7.87-7.74 (m, 1H), 7.64-7.60 (m, 1H),7.47-7.31 (m, 1H), 7.30-7.11 (m, 1H), 6.05 (d, J=7.8 Hz, 0.5H), 5.97 (d,J=7.0 Hz, 0.5H), 5.44-5.32 (m, 0.5H), 5.30-5.20 (m, 0.5H), 3.16-3.07 (m,5H), 3.06-2.91 (m, 1H), 2.77-2.58 (m, 4H), 2.38 (2×s, 3H), 2.22 (2×s,3H), 2.12-2.00 (m, 2H), 1.53-1.39 (m, 2H), 0.93-0.84 (m, 3H).

Example 140:(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclobutanecarboxamide(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

TEA (24.77 μL, 0.178 mmol) was added to a solution of N-propylamine(5.42 μL, 0.065 mmol),(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclobutanecarboxylicacid (30 mg, 0.059 mmol) and HATU (24.77 mg, 0.065 mmol) in DCM (3.81μL, 0.059 mmol) then stirred at rt for 24 h. The residue was dilutedwith water (10 mL) then extracted with DCM (50 mL). The organic phasewas washed with water (10 ml) then passed through a phase sep cartridgeand concentrated in vacuo. The residue was purified by chromatography(24 g silica, 0-10% methanol in DCM, gradient elution) to afford a 40:60mixture of(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclobutanecarboxamide(15 mg, 46%) as a colourless solid; Rt 2.00 min (method 1), m/z 548(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.45 (d, J=8.5 Hz, 0.5H), 8.12 (t,J=5.7 Hz, 0.5H), 7.96 (t, J=5.7 Hz, 0.5H), 7.91 (d, J=8.4 Hz, 0.5H),7.87-7.74 (m, 1H), 7.64-7.60 (m, 1H), 7.47-7.31 (m, 1H), 7.30-7.11 (m,1H), 6.05 (d, J=7.8 Hz, 0.5H), 5.97 (d, J=7.0 Hz, 0.5H), 5.44-5.32 (m,0.5H), 5.30-5.20 (m, 0.5H), 3.16-3.07 (m, 5H), 3.06-2.91 (m, 1H),2.77-2.58 (m, 4H), 2.38 (2×s, 3H), 2.22 (2×s, 3H), 2.12-2.00 (m, 2H),1.53-1.39 (m, 2H), 0.93-0.84 (m, 3H).

General Route D: Non-Convergent Approach Towards Valerolactam AnaloguesExample 146:(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide

DIPEA (0.623 mL, 3.57 mmol) was added to a solution of(R)-4-(3,5-dimethylisoxazol-4-yl)-N¹-(1-(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine(0.5 g, 1.427 mmol), HATU (0.705 g, 1.855 mmol) and(R)-6-oxopiperidine-2-carboxylic acid (0.225 g, 1.569 mmol) in DMF (5mL, 1.427 mmol) and stirred for 20 h. The mixture was evaporated invacuo and the residue dissolved in EtOAc (20 mL), washed with saturatedaqueous NaHCO₃ solution (20 mL), water (20 mL) and brine (10 mL), dried(MgSO4), filtered and evaporated in vacuo. The residual brown gum waspurified by chromatography on silica gel (40 g column, 0-10% MeOH in(50% DCM/EtOAc)) to give(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide(0.63 g, 93%) as a white solid; Rt 1.52 min (method 1), m/z 476 (M+H)+(ES+).

(R)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(R)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide(0.61 g, 1.283 mmol) was dissolved in TFA (20 mL, 1.283 mmol) andstirred at 70° C. for 3 days. The mixture was evaporated in vacuo andthe residual brown gum purified by flash chromatography (40 g column,0-20% MeOH in (50% DCM/EtOAc)) to give(R)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(0.53 g, 90%) as a colourless foam; Rt 2.00 min (method 1), m/z 602(M+H)+ (ES+).

(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.036 mL, 0.240 mmol) was added to a solution of(R)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.109 mmol) in dichloroethane (1 mL, 0.109 mmol) and stirred for10 min. CuTMEDA (18.78 mg, 0.040 mmol) was added, stirred for a 10 min,(3,4-dichlorophenyl)boronic acid (20.85 mg, 0.109 mmol) added and thereaction stirred for 20 h. The reaction was diluted with EtOAc (20 mL),washed with saturated aqueous NaHCO₃ solution (10 mL), water (10 mL) andbrine (5 mL), dried (MgSO₄), filtered and evaporated in vacuum. Theresidual gum was purified by flash chromatography (24 g column, 0-20%MeOH in (50% EtOAc/DCM)) to give(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (6 mg, 8%) asan off white solid; Rt 2.00 min (method 1), m/z 602 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.60 (d,J=2.4 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H),7.21 (dd, J=8.7, 2.4 Hz, 1H), 5.82 (t, J=4.5 Hz, 1H), 5.38 (p, J=8.6 Hz,1H), 3.70 (ddd, J=9.7, 6.9, 4.4 Hz, 1H), 3.56-3.30 (m, 4H), 3.06 (s,3H), 2.65-2.52 (m, 2H), 2.46 (d, J=8.2 Hz, 1H), 2.42 (s, 3H), 2.25 (s,3H), 2.15-2.06 (m, 2H), 1.89 (s, 1H), 1.80 (s, 1H).

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide

DIPEA (0.623 mL, 3.57 mmol) was added to a solution of(R)-4-(3,5-dimethylisoxazol-4-yl)-N¹-(1-(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine(0.5 g, 1.427 mmol), HATU (0.705 g, 1.855 mmol) and(S)-6-oxopiperidine-2-carboxylic acid (0.225 g, 1.569 mmol) in DMF (5ml, 1.427 mmol) and stirred for 20 h. The DMF was evaporated in vacuoand the residue dissolved in EtOAc (20 mL), washed with aqNaHCO3 (20mL), water (20 mL) and brine (10 mL), dried (MgSO4), filtered andevaporated in vacuo. The residual brown gum was purified by flashchromatography (40 g column, 0-10% MeOH in (50% DCM/EtOAc)) to give(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide(0.62 g, 90%) as a white foam; Rt 1.54 min (method 1), m/z 476 (M+H)+(ES+).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxopiperidine-2-carboxamide(0.6 g, 1.262 mmol) was dissolved in TFA (20 mL, 1.262 mmol) and stirredat 70° C. for 3 days. The mixture was concentrated in vacuo and theresidual brown gum purified by flash chromatography (40 g column, 0-20%MeOH in (50% DCM/EtOAc)) to give(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(0.53 g, 92%) as a white solid; Rt 1.52 min (method 2), m/z 458 (M+H)+(ES+).

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.036 mL, 0.240 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.109 mmol) in DCM (2 ml, 0.109 mmol), and stirred for 10 min.CuTMEDA (10.15 mg, 0.022 mmol) was added, sonicated and stirred for a 10min, (3,4-dichlorophenyl)boronic acid (41.7 mg, 0.219 mmol) added andthe reaction stirred for 48 h. The reaction was diluted with EtOAc (20ml), washed with aqNaHCO3 (10 ml), water (10 ml) and brine (5 ml), dried(MgSO4), filtered and evaporated in vacuum. The residual gum waspurified by chromatography on silica gel (24 g column, 0-20% MeOH in(50% EtOAc/DCM)) to give(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(18 mg, 27% yield as an off white solid; Rt 2.00 min (method 1), m/z 602(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.75 (d, J=1.6 Hz, 1H), 7.71 (d, J=8.5Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.29-7.19 (m,2H), 5.83 (t, J=4.7 Hz, 1H), 5.45-5.32 (m, 1H), 3.79 (dd, J=10.6, 8.9Hz, 1H), 3.70-3.57 (m, 2H), 3.33 (m, 2H), 3.08 (s, 3H), 2.67-2.52 (m,2H), 2.41 (s, 3H), 2.46-2.27 (m, 1H), 2.25 (s, 3H), 2.20-2.03 (m, 2H),1.91 (d, J=7.6 Hz, 1H), 1.79 (d, J=9.5 Hz, 1H).

Example 148:(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 mL, 0.361 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(75 mg, 0.164 mmol) in DCM (2 mL, 0.164 mmol), and stirred for 10 min.CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated and stirred for a 10min. (4-Chloro-3-fluorophenyl)boronic acid (57.2 mg, 0.328 mmol) wasadded and the reaction stirred at RT for 18 h. DBU (20 μl), CuTMEDA (10mg) and boronic acid (20 mg) were added and the reaction stirred at rtfor a further 7 hr. The mixture was concentrated under reduced pressurethen the crude product was purified by chromatography on silica gel (24g column, 0-10% MeOH/DCM) to afford(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(40 mg, 41%) as a light pink solid; Rt 1.95 min (method 1), m/z 586(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.75-7.72 (1H, m), 7.70 (1H, d, J=8.5Hz), 7.50 (1H, t, J=8.6 Hz), 7.37 (1H, dd, J=10.9, 2.3 Hz), 7.25 (1H,dd, J=8.5, 1.7 Hz), 7.11 (1H, ddd, J=8.6, 2.3, 1.0 Hz), 5.81 (1H, t,J=4.6 Hz), 5.45-5.30 (1H, m), 3.79 (1H, dd, J=10.6, 8.9 Hz), 3.68-3.57(2H, m), 3.32-3.25 (1H, m), 3.07 (3H, s), 2.65-2.51 (2H, m), 2.40 (3H,s), 2.39-2.26 (2H, m), 2.24 (3H, s), 2.19-2.09 (2H, m), 1.98-1.85 (1H,m), 1.83-1.72 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2%TFA): RT=8.96 min, >99% de @ 254 nm.

Example 149:(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 mL, 0.361 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(75 mg, 0.164 mmol) in DCM (2 mL, 0.164 mmol), and stirred for 10 min.CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated and stirred for a 10min. (3,4-Difluorophenyl)boronic acid (51.8 mg, 0.328 mmol) was addedand the reaction stirred at RT for 18 hr. The mixture was concentratedunder reduced pressure then the crude product was purified bychromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(39 mg, 40%) as a tan solid; Rt 1.86 min (method 1), m/z 570 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.75 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=8.4Hz), 7.42-7.29 (2H, m), 7.25 (1H, dd, J=8.5, 1.7 Hz), 7.11-7.02 (1H, m),5.76 (1H, t, J=4.7 Hz), 5.40-5.29 (1H, m), 3.81-3.73 (1H, m), 3.65-3.57(2H, m), 3.31-3.25 (1H, m), 3.06 (3H, s), 2.63-2.52 (2H, m), 2.41 (3H,s), 2.38-2.35 (1H, m), 2.35-2.26 (1H, m), 2.24 (3H, s), 2.16-2.08 (2H,m), 2.02-1.87 (1H, m), 1.84-1.72 (1H, m); Chiral HPLC (Diacel ChiralpakIA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=7.86 min, >99% de @ 254 nm.

Example 150:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 mL, 0.361 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(75 mg, 0.164 mmol) in DCM (2 mL, 0.164 mmol), and stirred for 10 min.CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated and stirred for a 10min. (3-Chloro-4-methoxyphenyl)boronic acid (61.1 mg, 0.328 mmol) wasadded and the reaction stirred at RT for 18 h. The mixture wasconcentrated under reduced pressure then the crude product was purifiedby chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (23 mg, 22%)as a pink solid; Rt 1.83 min (method 1), m/z 598 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.75 (1H, d, J=1.6 Hz), 7.68 (1H, d, J=8.4 Hz), 7.36 (1H,d, J=2.4 Hz), 7.24 (1H, dd, J=8.5, 1.7 Hz), 7.12 (1H, dd, J=8.8, 2.5Hz), 7.01 (1H, d, J=8.9 Hz), 5.73 (1H, t, J=4.8 Hz), 5.42-5.31 (1H, m),3.81-3.72 (4H, m), 3.66-3.54 (2H, m), 3.31-3.22 (1H, m), 3.06 (3H, s),2.61-2.52 (1H, m), 2.41 (3H, s), 2.39-2.29 (1H, m), 2.24 (3H, s),2.17-2.08 (2H, m), 2.06-1.89 (3H, m), 1.84-1.72 (1H, m); Chiral HPLC(Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min,isocratic 30% EtOH in isohexane (0.2% TFA): RT=11.53 min, >99% de @ 254nm.

Example 151:(S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 mL, 0.361 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(75 mg, 0.164 mmol) in DCM (2 mL, 0.164 mmol), and stirred for 10 min.CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated and stirred for a 10min. (3-Fluoro-4-methoxyphenyl)boronic acid (55.7 mg, 0.328 mmol) wasadded and the reaction stirred at RT for 18 h. The mixture wasconcentrated under reduced pressure then the crude product was purifiedby chromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford(S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (26 mg, 27%)as a tan solid; Rt 1.77 min (method 1), m/z 582 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.75 (1H, d, J=1.7 Hz), 7.68 (1H, d, J=8.6 Hz), 7.24 (1H,dd, J=8.5, 1.7 Hz), 7.12 (1H, dd, J=12.7, 2.4 Hz), 7.08-7.00 (1H, m),6.99-6.91 (1H, m), 5.70 (1H, d, J=5.0 Hz), 5.42-5.30 (1H, m), 3.80-3.70(4H, m), 3.66-3.53 (2H, m), 3.30-3.24 (1H, m), 3.06 (3H, s), 2.63-2.53(1H, m), 2.41 (3H, s), 2.39-2.32 (2H, m), 2.24 (3H, s), 2.16-2.08 (1H,m), 2.01 (3H, s), 1.84-1.70 (1H, m); Chiral HPLC (Diacel Chiralpak IA, 5μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): 156251D, RT=11.82 min, >99% de @ 254 nm.

Example 152:(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide

HATU (1061 mg, 2.79 mmol) was added to a solution of(S)-6-oxopiperidine-2-carboxylic acid (399 mg, 2.79 mmol), IntermediateC8 (800 mg, 2.54 mmol) and N,N-diisopropylethylamine (0.532 ml, 3.04mmol) in DMF (6 ml, 77 mmol) then stirred at room temperature overnight.The mixture was diluted with water (20 mL) then extracted with ethylacetate (3×50 mL). The combined organic phases were washed with 1M HCl(10 mL), Sat. NaHCO₃ (10 mL) and saturated brine (3×10 mL), then dried(MgSO₄), filtered and concentrated to give a brown oil. The crudeproduct was purified by chromatography on silica gel (40 g column, 0-10%MeOH/DCM) to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide (693 mg, 53%) as a pinksolid; Rt 1.64 min (method 1), m/z 441 (M+H)+ (ES+).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide (200 mg, 0.454 mmol) was heated to 80° C. inacetic acid (1040 μL, 18.16 mmol) for 24 h. The crude product was loadedonto a column of SCX (2 g) in MeOH. The column was washed with MeOH andthen the product was eluted with 7 M ammonia in MeOH. The resultantmixture was concentrated in vacuo to afford (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(120 mg, 62%) as a pink solid; Rt 1.71 min (method 1), m/z 423 (M+H)+(ES+).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one

DBU (0.080 mL, 0.531 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(120 mg, 0.241 mmol) in DCM (2 mL, 0.241 mmol), and stirred at RT for 10min. CuTMEDA (22.42 mg, 0.048 mmol) was added, sonicated and stirred atRT for a further 10 min. Then (3,4-difluorophenyl)boronic acid (76 mg,0.483 mmol) was added and the reaction stirred at RT for 18 hr. Themixture was concentrated under reduced pressure then the crude productwas purified by chromatography on silica gel (24 g column, 0-10%MeOH/DCM) to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-di-fluorophenyl)piperidin-2-one(37 mg, 28%) as a light pink solid; the enantiomers were separated bychiral preparative HPLC (General method E); Rt 2.07 min; m/z 535 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.78 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=1.6Hz), 7.42-7.28 (2H, m), 7.14 (1H, dd, J=8.5, 1.7 Hz), 7.08-7.01 (1H, m),5.77 (1H, t, J=4.6 Hz), 4.45-4.29 (1H, m), 3.45-3.34 (1H, m), 3.28 (3H,s), 2.63-2.52 (2H, m), 2.40 (3H, s), 2.37-2.28 (2H, m), 2.23 (3H, s),2.21-2.11 (2H, m), 2.07 (3H, s), 1.87-1.71 (2H, m), 1.46-1.29 (2H, m),1.29-1.17 (1H, m).

Example 153:(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.039 ml, 0.260 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.118 mmol) in DCM (0.2 mL, 0.118 mmol) and MeCN (2 mL, 38.3mmol), and stirred for 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added,sonicated and stirred for a 10 min, (4-chloro-3-fluorophenyl)boronicacid (41.3 mg, 0.237 mmol) added and the reaction stirred at 35° C. for24 h. The mixture was concentrated under reduced pressure then the crudeproduct was purified by chromatography on silica gel (24 g column, 0-10%MeOH/DCM) to afford(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(23 mg, 34%) as a light pink solid; Rt 2.17 min; m/z 551 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.50(t, J=8.6 Hz, 1H), 7.38 (dd, J=10.9, 2.3 Hz, 1H), 7.15 (dd, J=8.5, 1.7Hz, 1H), 7.09 (ddd, J=8.7, 2.3, 1.0 Hz, 1H), 5.85-5.79 (m, 1H),4.45-4.33 (m, 1H), 3.46-3.36 (m, 1H), 3.29 (s, 3H), 2.65-2.54 (m, 2H),2.41 (s, 3H), 2.39-2.27 (m, 2H), 2.24 (s, 3H), 2.20-2.10 (m, 2H),2.10-1.91 (m, 3H), 1.88-1.73 (m, 2H), 1.46-1.32 (m, 2H), 1.32-1.22 (m,1H). Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 min method,1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=5.69min, >99% de @ 254 nm.

Example 154:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.039 mL, 0.260 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.118 mmol) in DCM (0.2 mL, 0.118 mmol) and MeCN (2 mL, 38.3mmol), and stirred for 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added,sonicated and stirred for a 10 min, (3-chloro-4-methoxyphenyl)boronicacid (44.1 mg, 0.237 mmol) added and the reaction stirred at 35° C. for24 hr. The mixture was concentrated under reduced pressure then thecrude product was purified by chromatography on silica gel (24 g column,0-10% MeOH/DCM) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(20 mg, 29%) as a pink solid; Rt 2.02 min; m/z 563 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.38 (d,J=2.4 Hz, 1H), 7.13 (dd, J=8.5, 1.7 Hz, 1H), 7.09 (dd, J=8.8, 2.5 Hz,1H), 7.00 (d, J=9.0 Hz, 1H), 5.79-5.70 (m, 1H), 4.45-4.31 (m, 1H), 3.76(s, 3H), 3.45-3.35 (m, 1H), 3.28 (s, 3H), 2.64-2.53 (m, 1H), 2.41 (s,3H), 2.38-2.27 (m, 2H), 2.24 (s, 3H), 2.18-1.97 (m, 6H), 1.87-1.74 (m,2H), 1.49-1.28 (m, 2H), 1.18-1.09 (m, 1H); Chiral HPLC (Diacel ChiralpakIA, 5 μm, 4.6×250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH inisohexane (0.2% TFA): RT=7.00 min, >99% de @ 254 nm.

Example 155:(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

DBU (0.039 mL, 0.260 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.118 mmol) in DCM (0.2 mL, 0.118 mmol) and MeCN (2 mL, 38.3mmol), and stirred for 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added,sonicated and stirred for a 10 min, (3-fluoro-4-methoxyphenyl)boronicacid (40.2 mg, 0.237 mmol) added and the reaction stirred at 35° C. for24 hr. The mixture was concentrated under reduced pressure then thecrude product was purified by chromatography on silica gel (24 g column,0-10% MeOH/DCM) to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(25 mg, 37%) as a tan solid; Rt 1.94 min; m/z 547 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.76 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=1.6 Hz), 7.16-7.07(2H, m), 7.07-6.98 (1H, m), 6.98-6.92 (1H, m), 5.75-5.68 (1H, m),4.42-4.28 (1H, m), 3.74 (3H, s), 3.46-3.36 (1H, m), 3.28 (3H, s),2.64-2.52 (2H, m), 2.40 (3H, s), 2.37-2.27 (2H, m), 2.24 (3H, s),2.20-1.95 (5H, m), 1.77 (2H, d, J=11.6 Hz), 1.49-1.26 (2H, m), 1.20-1.07(1H, m); Chiral HPLC (Diacel Chiralpak IA, 5 μm, 4.6×250 mm, 30 minmethod, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA): RT=7.58min, >99% de @ 254 nm.

Example 156:(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide

HATU (900 mg, 2.367 mmol) was added to a stirred solution of TEA (0.35mL, 2.51 mmol), (S)-6-oxopiperidine-2-carboxylic acid (350 mg, 2.445mmol) and Intermediate C24 (710 mg, 2.206 mmol) in N,N-dimethylformamide(10 mL) then the mixture was stirred at room temperature for 2 h. Themixture was diluted with brine (100 mL) then extracted with ethylacetate (3×100 mL). The combined organic phases were concentrated underreduced pressure. The crude product was purified by chromatography onthe Companion (40 g column, 50-100% THF/DCM) then triturated in diethylether to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide(822 mg, 80%) as a white solid; Rt 1.62 min; m/z 441 (M+H)+ (ES+).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide(800 mg, 1.780 mmol) was heated to 80° C. in acetic acid (20 mL) for 4h. The acetic acid was removed under reduced pressure then the residuewas dissolved in DCM:MeOH:diethylamine (25 mL, 8:1:1) and concentratedonto loose silica gel. The silicate was purified by chromatography onthe Companion (40 g column, 15-75% DCM/THF) then triturated in diethylether to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(480 mg, 61%) as a white solid; Rt 1.26 min; m/z 423 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.75 (d, J=8.5 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.65(d, J=1.5 Hz, 1H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 5.12-5.00 (m, 1H),4.50-4.36 (m, 1H), 4.43 (s, 1H), 2.71-2.54 (m, 2H), 2.41 (s, 3H),2.31-2.24 (m, 2H), 2.24 (s, 3H), 2.17-2.03 (m, 1H), 1.92-1.49 (m, 9H),1.21 (s, 3H).

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.166 mmol), (3,4-difluorophenyl)boronic acid (30 mg, 0.190mmol) and DBU (27 μL, 0.179 mmol) were heated to 70° C. in acetonitrile(2 mL) for 18 h. The mixture was concentrated onto loose silica gel. Thesilicate was purified by chromatography on the Companion (12 g column,0-50% THF/DCM) then purified further on the Companion (4 g column, 1-4%MeOH/DCM) to afford(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(35 mg, 37%) as an off-white solid; the enantiomers were separated bychiral preparative HPLC (General method A); Rt 1.82 min; m/z 535 (M+H)+(ES+); 1H NMR (d₆-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.68 (d, J=8.6 Hz,1H), 7.41-7.29 (m, 2H), 7.22 (dd, J=8.4, 1.7 Hz, 1H), 7.08-6.99 (m, 1H),5.75-5.70 (m, 1H), 4.42 (s, 1H), 4.41-4.28 (m, 1H), 2.64-2.52 (m, 2H),2.48-2.31 (m, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 2.10-1.90 (m, 2H),1.84-1.43 (m, 6H), 1.18 (s, 3H), 1.07-0.91 (m, 1H).

Example 157:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.166 mmol), (3-chloro-4-methoxyphenyl)boronic acid (35 mg,0.188 mmol) and DBU (27 μl, 0.179 mmol) were heated to 70° C. inacetonitrile (2 mL) for 18 h. The mixture was concentrated onto loosesilica gel. The silicate was purified by chromatography on the Companion(12 g column, 0-50% THF/DCM) then purified further on the Companion (4 gcolumn, 1-4% MeOH/DCM) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(25 mg, 0.042 mmol, 25.5% yield) as an off white solid; Rt 1.79 min; m/z563 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.20 (dd, J=8.5, 1.7 Hz, 1H),7.09 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 5.74-5.65 (m, 1H),4.41 (s, 1H), 4.40-4.27 (m, 1H), 3.75 (s, 3H), 2.62-2.52 (m, 2H),2.48-2.29 (m, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 2.11-1.93 (m, 2H),1.84-1.72 (m, 1H), 1.72-1.64 (m, 1H), 1.63-1.44 (m, 4H), 1.18 (s, 3H),0.97-0.84 (m, 1H).

Example 158:(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.166 mmol), (3,4-dichlorophenyl)boronic acid (35 mg, 0.183mmol) and DBU (27 μL, 0.179 mmol) were heated to 70° C. in acetonitrile(2 mL) for 18 h. The mixture was concentrated onto loose silica gel. Thesilicate was purified by chromatography on the Companion (12 g column,0-50% THF/DCM) then purified further on the Companion (4 g column,1.5-4% MeOH/DCM) to afford(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(19 mg, 19%) as a white solid; Rt 2.01 min; m/z 567 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.72-7.66 (m, 2H), 7.62 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.22 (dd, J=8.4, 1.7 Hz, 1H), 7.18 (dd, J=8.7, 2.4 Hz, 1H),5.81 (t, J=4.7 Hz, 1H), 4.44 (s, 1H), 4.42-4.31 (m, 1H), 2.66-2.53 (m,3H), 2.49-2.42 (m, 1H), 2.41 (s, 3H), 2.39-2.32 (m, 1H), 2.25 (s, 3H),2.10-1.89 (m, 2H), 1.84-1.74 (m, 1H), 1.74-1.66 (m, 1H), 1.66-1.46 (m,4H), 1.19 (s, 3H), 1.07-0.95 (m, 1H).

Example 159:(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.166 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (32 mg,0.188 mmol) and DBU (27 μL, 0.179 mmol) were heated to 70° C. inacetonitrile (2 mL) for 18 h. The mixture was concentrated onto loosesilica gel. The silicate was purified by chromatography on the Companion(12 g column, 0-50% THF/DCM) then purified further on the Companion (4 gcolumn, 1.5-4% MeOH/DCM) to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(18 mg, 19%) as a white solid; Rt 1.72 min; m/z 547 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.21 (dd,J=8.4, 1.7 Hz, 1H), 7.13 (dd, J=12.8, 2.4 Hz, 1H), 7.03 (dd, J=9.2 Hz,1H), 6.95 (ddd, J=8.8, 2.4, 1.2 Hz, 1H), 5.69 (t, J=4.5 Hz, 1H), 4.42(s, 1H), 4.40-4.27 (m, 1H), 3.74 (s, 3H), 2.62-2.53 (m, 2H), 2.49-2.43(m, 1H), 2.42 (s, 3H), 2.41-2.28 (m, 2H), 2.25 (s, 3H), 2.10-1.96 (m,2H), 1.84-1.42 (m, 6H), 1.18 (s, 3H), 1.00-0.79 (m, 1H).

Example 160:(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.166 mmol), (4-chloro-3-fluorophenyl)boronic acid (32 mg, 0.184mmol) and DBU (27 μl, 0.179 mmol) were heated to 70° C. in acetonitrile(2 mL) for 18 h. The mixture was concentrated onto loose silica gel. Thesilicate was purified by chromatography on the Companion (12 g column,0-50% THF/DCM) then purified further on the Companion (4 g column,1.5-4% MeOH/DCM) to afford((S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(20 mg, 21%) as a white solid; Rt 1.93 min; m/z 551 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.74-7.66 (m, 2H), 7.50 (dd, J=8.6 Hz, 1H), 7.38 (dd,J=10.9, 2.3 Hz, 1H), 7.23 (dd, J=8.5, 1.6 Hz, 1H), 7.08 (ddd, J=8.7,2.3, 1.0 Hz, 1H), 5.79 (t, J=4.6 Hz, 1H), 4.44 (s, 1H), 4.37 (t, J=12.3Hz, 1H), 2.65-2.52 (m, 3H), 2.49-2.43 (m, 1H), 2.41 (s, 3H), 2.40-2.32(m, 1H), 2.25 (s, 3H), 2.10-1.89 (m, 2H), 1.84-1.44 (m, 6H), 1.19 (s,3H), 1.08-0.98 (m, 1H).

Example 161:(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-6-oxopiperidine-2-carboxamide

TEA (3.06 mL, 21.95 mmol) was added to a solution of(1r,3r)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclobutanol(2 g, 7.32 mmol), (S)-6-oxopiperidine-2-carboxylic acid (1.152 g, 8.05mmol) and HATU (3.06 g, 8.05 mmol) in DMF (20 mL) then stirred at roomtemperature for 18 hrs. The mixture was concentrated on the rotovap toremove the bulk of the DMF. The loose residue was diluted with DCM (200ml) and washed with water (2×50 mL). The organic phase was collected viaphase sep cartridge and concentrated in vacuo to afford a viscous orangeoil. The crude material was purified by chromatography (80 g silica,0-10% MeOH in DCM, gradient elution). Product fractions wereconcentrated in vacuo to afford(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-6-oxopiperidine-2-carboxamide(587 mg, 20%) as a brown/yellow sticky solid/foam; Rt 1.38 min; m/z 399(M+H)+ (ES+).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(S)—N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-6-oxopiperidine-2-carboxamide (585 mg, 1.468 mmol) was dissolved in aceticacid (2 mL) and stirred at 80° C. for 18 hrs. The reaction mixture wascooled to RT and the solvent was removed in vacuo. The residue waspurified by chromatography (12 g silica, 0-10% methanol in DCM, gradientelution). Product fractions were combined and concentrated in vacuo toafford the crude(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(950 mg) as a light brown solid; Rt 1.18 min; m/z 381 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (83 μL, 0.552 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and(3,4-difluorophenyl)boronic acid (91 mg, 0.578 mmol) in acetonitrile (2mL). The reaction mixture was stirred for 18 h at 40° C., thenconcentrated under reduced pressure. DCM and silica was added and thesolvent removed in vacuo. The crude product (adsorbed to silica) waspurified by chromatography (12 g silica, 0-10% MeOH in DCM, gradientelution) to afford(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (97 mg, 36%) as a lightyellow glass which scratched to a crystalline solid; Rt 1.70 min; m/z493 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.81-7.69 (m, 2H), 7.40 (ddd,J=12.0, 7.4, 2.5 Hz, 1H), 7.33 (dt, J=10.7, 9.0 Hz, 1H), 7.19 (dd,J=8.5, 1.7 Hz, 1H), 7.14-7.05 (m, 1H), 6.55 (s, 1H), 5.68 (dd, J=5.4,4.0 Hz, 1H), 5.37-5.24 (m, 2H), 4.54 (s, 1H), 2.98 (dt, J=12.8, 7.8 Hz,1H), 2.86 (dt, J=15.0, 7.7 Hz, 1H), 2.60-2.46 (m, 2H), 2.40 (m, 4H),2.23 (s, 3H), 2.19 (m, 1H), 2.03 (m, 1H), 1.91-1.71 (m, 2H).

Example 162:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (83 μL, 0.552 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (108 mg, 0.578 mmol) inacetonitrile (2 mL). The reaction mixture was stirred for 18 h at 40°C., then concentrated under reduced pressure. DCM and silica was addedand the solvent removed in vacuo. The crude product (adsorbed to silica)was purified by chromatography (12 g silica, 0-10% MeOH in DCM, gradientelution) and sonicated with ether (removing the solvent in vacuo) toafford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(52 mg, 17%) as a light yellow solid; Rt 1.69 min; m/z 521 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.80-7.69 (m, 2H), 7.38 (d, J=2.5 Hz, 1H), 7.22-7.12(m, 2H), 7.00 (d, J=8.9 Hz, 1H), 5.64 (t, J=4.8 Hz, 1H), 5.36-5.27 (m,2H), 4.53 (s, 1H), 3.75 (s, 3H), 2.98 (dt, J=12.7, 7.7 Hz, 1H), 2.84(dt, J=14.9, 7.7 Hz, 1H), 2.60-2.35 (m, 4H), 2.40 (s, 3H), 2.24 (s, 3H),2.27-2.15 (m, 1H), 2.01 (s, 1H), 1.88 (s, 1H), 1.77 (s, 1H).

Example 163:(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (83 μL, 0.552 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and(3,4-dichlorophenyl)boronic acid (110 mg, 0.578 mmol) in acetonitrile (2mL). The reaction mixture was stirred for 18 h at 40° C., thenconcentrated under reduced pressure. DCM and silica was added and thesolvent removed in vacuo. The crude product (adsorbed to silica) waspurified by chromatography (12 g silica, 0-10% MeOH in DCM, gradientelution) and sonicated with ether (removing the solvent in vacuo) toafford(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (71 mg, 25%) as a lightyellow solid; Rt 1.90 min; m/z 525 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ:7.78 (d, J=8.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H),7.53 (d, J=8.7 Hz, 1H), 7.22 (ddd, J=21.6, 8.6, 2.0 Hz, 2H), 5.74 (t,J=4.7 Hz, 1H), 5.32 (q, J=8.7 Hz, 2H), 4.55 (t, J=7.1 Hz, 1H), 2.99 (dt,J=12.6, 7.7 Hz, 1H), 2.87 (dt, J=12.5, 7.6 Hz, 1H), 2.63-2.45 (m, 2H),2.44-2.35 (m, 5H), 2.27-2.21 (m, 5H), 2.07-1.99 (m, 1H), 1.85-1.75 (m,1H).

Example 164:(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (13.79 mg, 0.030 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(96.5 mg, 0.228 mmol), (3,4-difluorophenyl)boronic acid (54.1 mg, 0.343mmol) and DBU (0.038 ml, 0.251 mmol) in acetonitrile (3.0 ml, 57.4 mmol)were heated to 70° C. for 6 h. (3,4-Difluorophenyl)boronic acid (20 mg)was added and stirring continued at the same temperature for a further16 h. The mixture was concentrated onto loose silica gel. The silicatewas purified by chromatography on the Companion (12 g column, 1-3%;isocratic 3% then 10% MeOH/DCM) to afford(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(56 mg, 44%) as a brown yellow solid; Rt 1.84 min; m/z 535 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39(ddd, 1H), 7.36-7.29 (m, 1H), 7.21-7.17 (m, 1H), 7.08-7.02 (m, 1H),5.80-5.76 (m, 1H), 4.58 (s, 1H), 4.41-4.28 (m, 1H), 2.64-2.52 (m, 2H),2.40 (s, 3H), 2.39-2.30 (m, 1H), 2.24 (s, 3H), 2.21-2.07 (m, 2H),2.06-1.92 (m, 2H), 1.83-1.72 (m, 2H), 1.70-1.56 (m, 4H), 1.32 (s, 3H),1.15 (dd, J=12.8, 8.8 Hz, 1H).

Example 165:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (13.79 mg, 0.030 mmol) was added to a solution of(3-chloro-4-methoxyphenyl)boronic acid (63.9 mg, 0.343 mmol),(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(96.5 mg, 0.228 mmol) and DBU (0.038 ml, 0.251 mmol) in acetonitrile(3.0 mL, 57.4 mmol) were heated to 70° C. for 6 h then more(3-chloro-4-methoxyphenyl)boronic acid (20 mg) was added and stirringcontinued for 22 h. CuTMEDA (14 mg) was added and the reaction washeated for a further 3 h. The mixture was concentrated onto loose silicagel. The silicate was purified by chromatography on the Companion (12 gcolumn, 1-3%; isocratic then 10% MeOH/DCM) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(52.7 mg, 39%) as a brown yellow solid; Rt 1.81 min; m/z 564 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.71 (d, J=1.7 Hz, 1H), 7.60 (d, J=8.5 Hz,1H), 7.39 (d, J=2.4 Hz, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 7.09 (dd,J=8.8, 2.5 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 5.74 (t, 1H), 4.57 (s, 1H),4.40-4.29 (m, 1H), 3.75 (s, 3H), 2.61-2.52 (m, 2H), 2.41 (s, 3H),2.38-2.30 (m, 1H), 2.26-2.13 (m+s, 1H), 2.11-1.96 (m, 3H), 1.85-1.75 (m,1H), 1.74-1.64 (m, 4H), 1.63-1.54 (m, 1H), 1.31 (s, 3H), 1.09-1.01 (m,1H).

Example 166:(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

CuTMEDA (13.79 mg, 0.030 mmol) was added to a solution of(3-fluoro-4-methoxyphenyl)boronic acid (58.2 mg, 0.343 mmol),(3-fluoro-4-methoxyphenyl)boronic acid (58.2 mg, 0.343 mmol) and DCM(0.30 ml, 4.66 mmol) in acetonitrile (3.0 ml, 57.4 mmol) were heated to70° C. for 6 h. 3-Fluoro-4-methoxyphenyl)boronic acid (20 mg) was addedafter 6h of heating then the mixture stirred for 22 h at the sametemperature before more CuTMEDA (14 mg) was added and the reaction washeated for a further 3h. The mixture was concentrated onto loose silicagel. The silicate was purified by chromatography on the Companion (12 gcolumn, 1-3% MeOH/DCM then isocratic and up to 10% MeOH) to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (52 mg, 40%)as a beige solid; the enantiomers were separated by chiral preparativeHPLC (General method C); Rt 1.71 min; m/z 507 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.18 (dd,J=8.5, 1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.4 Hz, 1H), 7.02 (t, J=9.1 Hz,1H), 6.96 (ddd, J=2.4, 1.1 Hz, 1H), 5.72 (t, 1H), 4.57 (s, 1H),4.39-4.27 (m, 1H), 3.73 (s, 3H), 2.57-2.52 (m, 1H), 2.47-2.29 (m+s, 5H),2.28-2.16 (m+s, 4H), 2.14-1.96 (m, 3H), 1.84-1.67 (m, 4H), 1.62-1.56 (m,2H), 1.34-1.29 (s, 3H), 1.02 (m, 1H).

Example 167:(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (86 μL, 0.573 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol) and(3,4-dichlorophenyl)boronic acid (115 mg, 0.600 mmol) in acetonitrile (3mL). The reaction mixture was stirred for 18 h at 40° C., and thenconcentrated under reduced pressure. DCM and silica was added and thesolvent removed in vacuo. The crude product (adsorbed to silica) waspurified by chromatography (12 g silica, 0-10% MeOH in DCM, gradientelution). Product fractions were combined and concentrated in vacuo. Theresidue was sonicated with ether and the solid collected by filtrationto (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(49 mg, 17%) as a light beige solid; Rt 2.37 min; m/z 511 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.18(dd, J=8.5, 1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.4 Hz, 1H), 7.02 (t, J=9.1Hz, 1H), 6.96 (ddd, J=2.4, 1.1 Hz, 1H), 5.72 (t, 1H), 4.57 (s, 1H),4.39-4.27 (m, 1H), 3.73 (s, 3H), 2.57-2.52 (m, 1H), 2.47-2.29 (m+s, 5H),2.28-2.16 (m+s, 4H), 2.14-1.96 (m, 3H), 1.84-1.67 (m, 4H), 1.62-1.56 (m,2H), 1.34-1.29 (s, 3H), 1.02 (m, 1H).

Example 168:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (86 μL, 0.573 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol) and(3-chloro-4-methoxyphenyl)boronic acid (112 mg, 0.600 mmol) inacetonitrile (3 mL). The reaction mixture was stirred for 18 h at 40°C., and then concentrated under reduced pressure. DCM and silica wasadded and the solvent removed in vacuo. The crude product waspre-adsorbed to silica and purified by chromatography (12 g silica,0-10% MeOH in DCM, gradient elution) and finally sonicated with diethylether (removing the solvent in vacuo) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(55 mg, 19%) as a light pink/purple solid; Rt 2.14 min; m/z 507 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: Rt 2.14 min; m/z 547 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.73 (dd, J=1.6, 0.6 Hz, 1H), 7.57 (dd, J=8.4, 0.7 Hz, 1H),7.31 (d, J=2.5 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 7.11 (dd, J=8.8,2.5 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 5.51 (dd, J=5.6, 3.1 Hz, 1H), 3.95(dd, J=14.6, 6.8 Hz, 1H), 3.89 3.73 (m, 1H), 3.74 (s, 3H), 3.17 (d,J=4.0 Hz, 1H), 2.62-2.52 (m, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.10 (d,J=9.9 Hz, 1H), 2.06-1.97 (m, 1H), 1.95-1.79 (m, 1H), 1.77-1.70 (m, 1H),1.62 (s, 1H), 0.75 (d, J=6.6 Hz, 3H), 0.48 (d, J=6.6 Hz, 3H).

Example 169:(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

DBU (86 μL, 0.573 mmol) was added to a solution of(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one(200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol) and(3-fluoro-4-methoxyphenyl)boronic acid (102 mg, 0.600 mmol) inacetonitrile (3 mL). The reaction mixture was stirred for 18 h at 40°C., and then concentrated under reduced pressure. DCM and silica wasadded and the solvent removed in vacuo. The crude product (adsorbed tosilica) was purified by chromatography (12 g silica, 0-10% MeOH in DCM,gradient elution) and sonicated with ether (removing the solvent invacuo) to afford(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(27 mg, 10%) as a light pink/purple solid; the enantiomers wereseparated by chiral preparative HPLC (General method F); Rt 2.06 min;m/z 491 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: δ 7.73 (dd, J=1.6, 0.6 Hz,1H), 7.57 (dd, J=8.4, 0.6 Hz, 1H), 7.18 (dd, J=8.3, 1.6 Hz, 1H),7.11-6.90 (m, 3H), 5.49 (dd, J=5.5, 3.1 Hz, 1H), 3.94 (dd, J=14.5, 6.7Hz, 1H), 3.83 (dd, J=14.5, 8.7 Hz, 1H), 3.73 (s, 3H), 2.56 (dd, J=13.4,5.2 Hz, 1H), 2.41 (s, 3H), 2.35 (m, 1H), 2.25 (s, 3H), 2.15-1.97 (m,2H), 1.95-1.79 (m, 1H), 1.74 (m, 1H), 0.76 (d, J=6.6 Hz, 3H), 0.48 (d,J=6.6 Hz, 3H).

Example 170:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)—N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide

HATU (1.4 g, 3.68 mmol) was added to a stirred solution of TEA (0.6 ml,4.30 mmol), (S)-6-oxopiperidine-2-carboxylic acid (500 mg, 3.49 mmol)and Intermediate C12 (1.0 g, 3.11 mmol) in N,N-dimethylformamide (10 mL)then the mixture was stirred at room temperature for 2 h. The mixturewas concentrated under reduced pressure then purified by chromatographyon the Companion (40 g column, 0-25% THF/DCM) and triturated in diethylether to afford(S)—N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide(1.5 g, 97%) as a white solid; Rt 1.94 min; m/z 447 (M+H)+ (ES+).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

(S)—N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide(1.5 g, 3.02 mmol) was heated to 80° C. in acetic acid (25 mL) for 18 h.The solvents were removed under reduced pressure then the residue wasdissolved in DCM:MeOH:DEA (20:2.5:2.5, 25 mL) and concentrated ontoloose silica gel. The silicate was purified by chromatography on theCompanion (40 g column, 15-75% THF/DCM) then triturated in diethyl etherto afford(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(878 mg, 67%) as a white solid; Rt 1.78 min; m/z 429 (M+H)+ (ES+).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

CuTMEDA (55 mg, 0.118 mmol) was added to a suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(100 mg, 0.233 mmol) in pyridine (5 mL) then stirred at 40° C. for 15minutes. (3-fluoro-4-methoxyphenyl)boronic acid (100 mg, 0.588 mmol) wasadded then the mixture was stirred at 40° C. for 2 h. The mixture wasdiluted with ethyl acetate (25 mL) then washed with water (3×25 mL) andsaturated brine (25 mL). The organic phase was dried (MgSO4), filteredand concentrated under reduced pressure. The crude product was purifiedby chromatography on the Companion (12 g column, 0-25% THF) thentriturated in diethyl ether to afford(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(106 mg, 81%) as a white solid; the enantiomers were separated by chiralpreparative HPLC (General method B); Rt 2.18 min; m/z 597 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.22(dd, J=8.5, 1.7 Hz, 1H), 7.10 (dd, J=12.7, 2.4 Hz, 1H), 7.05 (dd, J=9.2Hz, 1H), 6.95 (ddd, J=8.8, 2.4, 1.2 Hz, 1H), 5.76-5.60 (m, 1H),4.74-4.56 (m, 1H), 3.75 (s, 3H), 2.63-2.52 (m, 2H), 2.41 (s, 3H),2.39-2.26 (m, 2H), 2.25 (s, 3H), 2.24-1.85 (m, 8H), 1.83-1.73 (m, 1H),1.30-1.18 (m, 1H).

Example 171:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one

CuTMEDA (28 mg, 0.060 mmol) was added to a stirred solution of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.116 mmol) and DBU (35 μL, 0.232 mmol) in acetonitrile (2 mL)then the mixture was stirred for 30 minutes. (3,4-difluorophenyl)boronicacid (35 mg, 0.222 mmol) was added then the mixture was heated to 50° C.overnight. The mixture was concentrated onto loose silica under reducedpressure. The crude product was purified by chromatography on theCompanion (12 g column, 5-25% THF/DCM) to afford(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one(35 mg, 53%) as a white solid; Rt 2.27 min; m/z 541 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.43-7.29(m, 2H), 7.23 (dd, J=8.5, 1.7 Hz, 1H), 7.11-6.97 (m, OH), 5.79-5.67 (m,1H), 4.75-4.56 (m, 1H), 2.67-2.52 (m, 2H), 2.48-2.42 (m, 1H), 2.41 (s,3H), 2.40-2.26 (m, 3H), 2.24 (s, 3H), 2.23-2.03 (m, 5H), 2.03-1.90 (m,2H), 1.85-1.73 (m, 1H), 1.44-1.30 (m, 1H).

Example 172:(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

CuTMEDA (50 mg, 0.108 mmol) was added to a suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(75 mg, 0.175 mmol) in pyridine (5 mL) then stirred at 40° C. for 15minutes. (3-Chloro-4-methoxyphenyl)boronic acid (100 mg, 0.536 mmol) wasadded then the mixture was stirred at 40° C. for 2 h. The mixture wasdiluted with ethyl acetate (25 mL) then washed with water (3×25 mL) andsaturated brine (25 mL). The organic phase was dried (MgSO₄), filteredand concentrated under reduced pressure. The crude product was purifiedby flash chromatography on the Companion (12 g column, 0-25% THF) thentriturated in diethyl ether to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (35 mg, 0.060mmol, 34.4% yield) as a white solid; Rt 2.26 min; m/z 569 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.37(d, J=2.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.08 (dd, J=8.8, 2.5Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 5.74-5.67 (m, 1H), 4.74-4.58 (m, 1H),3.76 (s, 3H), 2.65-2.53 (m, 2H), 2.45-2.25 (m, 6H), 2.24 (s, 3H),2.23-1.98 (m, 6H), 1.98-1.88 (m, 1H), 1.85-1.74 (m, 1H), 1.30-1.13 (m,1H).

Example 173:(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

To a scintillation vial containing(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(157 mg, 0.384 mmol) in pyridine (3 mL) was added CuTMEDA (89 mg, 0.192mmol). The reaction mixture was stirred at 40° C. for 15 minutes, then(3,4-dichlorophenyl)boronic acid (183 mg, 0.961 mmol) added and thereaction mixture was left to stir at 80° C. for 48 h. Rt 1.86 min; m/z521 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.69 (d,J=1.6 Hz, 1H), 7.43-7.27 (m, 2H), 7.13 (dd, J=8.5, 1.7 Hz, 1H), 7.04(ddd, J=9.1, 4.0, 1.9 Hz, 1H), 5.80-5.73 (m, 1H), 4.71 (d, J=4.1 Hz,1H), 4.31 (t, J=12.4 Hz, 1H), 3.74-3.53 (m, 1H), 2.63-2.50 (m, 2H), 2.40(m, 5H), 2.23 (m, 6H), 2.03 (d, J=13.4 Hz, 2H), 2.01-1.91 (m, 2H), 1.86(d, J=12.3 Hz, 1H), 1.81-1.65 (m, 1H), 1.35 (m, 4H).

Example 174:(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

To a scintillation vial containing(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (157 mg, 0.384mmol) in pyridine (3 mL) was added CuTMEDA (89 mg, 0.192 mmol). Thereaction mixture was stirred at 40° C. for 15 minutes, then(3,4-difluorophenyl)boronic acid (152 mg, 0.961 mmol) added and thereaction mixture was left to stir at 80° C. for 48 h. The reactionmixture was cooled to RT and partitioned between ethyl acetate (20 mL)and water (10 mL). The organic phase was washed with further portions ofwater (2×10 mL), dried (MgSO4) and concentrated in vacuo. The cruderesidue was purified by chromatography (4 g silica, 0-10% MeOH in DCM,gradient elution) to afford(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(54 mg, 27%) as an off white solid; the enantiomers were separated bychiral preparative HPLC (General method D); Rt 1.86 min; m/z 521 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.6 Hz,1H), 7.43-7.27 (m, 2H), 7.13 (dd, J=8.5, 1.7 Hz, 1H), 7.04 (ddd, J=9.1,4.0, 1.9 Hz, 1H), 5.80-5.73 (m, 1H), 4.71 (d, J=4.1 Hz, 1H), 4.31 (t,J=12.4 Hz, 1H), 3.74-3.53 (m, 1H), 2.63-2.50 (m, 2H), 2.40 (m, 5H), 2.23(m, 6H), 2.03 (d, J=13.4 Hz, 2H), 2.01-1.91 (m, 2H), 1.86 (d, J=12.3 Hz,1H), 1.81-1.65 (m, 1H), 1.35 (m, 4H).

Example 175:(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

To a scintillation vial containing(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(157 mg, 0.384 mmol) in pyridine (3 mL) was added CuTMEDA (89 mg, 0.192mmol). The reaction mixture was stirred at 40° C. for 15 minutes, then(3,4-dichlorophenyl)boronic acid (183 mg, 0.961 mmol) added and thereaction mixture was left to stir at 80° C. for 48 h.

Example 176:(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-oneTrans-(1r,4r)-4-((4-bromo-2-nitrophenyl)amino)cyclohexanol

4-Bromo-1-fluoro-2-nitrobenzene (2.85 mL, 23.14 mmol),trans-(1r,4r)-4-aminocyclohexanol (4.00 g, 34.7 mmol) and TEA (6.45 mL,46.3 mmol) were heated to reflux in THF (83 mL, 1018 mmol) for 48 h. Thereaction was cooled down to RT, then the solvents were evaporated invacuo and the orange residue was partitioned between EtOAc (100 mL) andDCM (100 mL) and saturated aqueous NaHCO₃ (100 mL) and the layersseparated. The aqueous phase was extracted with further DCM (2×100 mL)and the combined organic extracts washed with water (100 mL) and brine(100 mL). The solution was concentrated onto loose silica gel. Thesilicate was purified by chromatography on the Companion (80 g column,0-100% EtOAc/isohexane to affordtrans-(1r,4r)-4-((4-bromo-2-nitrophenyl)amino) cyclohexanol (5.79, 78%)was isolated as an orange solid; Rt 2.22 min; m/z 316 (M+H)+ (ES+).

Trans-(1r,4r)-4-((2-amino-4-bromophenyl)amino)cyclohexanol

Trans-(1r,4r)-4-((4-bromo-2-nitrophenyl)amino)cyclohexanol (5.79 g,18.37 mmol) and ammonium hydroxide (11.45 ml, 294 mmol) were dissolvedin THF (175 ml, 2131 mmol) and WATER (174 ml, 9682 mmol), SODIUMDITHIONATE (37.9 g, 184 mmol) was added and the reaction mixture stirredat RT overnight. The layers were separated, the aqueous extracted withEtOAc (100 mL), the combined organics washed with brine (50 mL), dried(MgSO₄), filtered and evaporated in vacuo to givetrans-(1r,4r)-4-((2-amino-4-bromophenyl)amino)cyclohexanol (3.87 g, 72%)as a pink solid; Rt 1.16 min; m/z 285 (M+H)+ (ES+).

(S)—N-(5-bromo-2-((trans-(1r,4r)-4-hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

DIPEA (1.646 mL, 9.42 mmol) was added to a solution oftrans-(1r,4r)-4-((2-amino-4-bromophenyl)amino)cyclohexanol (1.8 g, 6.31mmol), (S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid(1.0 g, 4.15 mmol) and HATU (1.863 g, 4.90 mmol) in DMF (12.55 ml, 162mmol). The brown solution was stirred at RT for 15 h. The mixture waspartitioned between ethyl acetate (100 mL) and water (100 mL), then thelayers separated. The organic phase was washed with water (3×100 mL) andwith brine (100 mL), concentrated in vacuo to give a crude dark oil (3.3g), which was purified by flash chromatography on the Companion (40 gcolumn, 0-10% MeOH/DCM) to afford(S)—N-(5-bromo-2-((trans-(1r,4r)-4-hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide (1.36 g, 68%) as a grey purple foam; Rt 1.98 min;m/z 508 (M+H)+ (ES+).

trans-(1r,4r)-4-(5-bromo-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate

(S)—N-(5-bromo-2-((trans-(1r,4r)-4-hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide(1.36 g, 2.68 mmol) was dissolved in acetic acid (10.72 mL, 187 mmol)and stirred at 70° C. for 72 h. The reaction was cooled down to RT andconcentrated in vacuo. The crude brown oil was purified by flashchromatography on the Companion (4 g, DCM/MeOH: 100/0 to 90/10). Therelevant fractions were concentrated and the residue dissolved in DCM(50 mL) and washed with a saturated solution of NaHCO₃ (2*50 mL). Theorganic was dried on a phase layer separator and concentrated in vacuoto give(S)-5-(5-bromo-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(365 mg, 26%) was isolated as a beige solid; Rt 2.36 min; m/z 534 (M+H)+(ES+).

trans-(1r,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate 1555-88

To a solution oftrans-(1r,4r)-4-(5-bromo-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate (0.345 g, 0.648 mmol) and Bis-(pinacolato) diboron (0.247 g,0.972 mmol) in 1,4-dioxane (5.40 ml, 0.648 mmol) was added potassiumdicarbonate (0.204 g, 2.074 mmol) and PdCl₂(dppf) (0.045 g, 0.062 mmol).The mixture was degassed with nitrogen and heated at 85° C. for 2 h andthen cooled to RT and concentrated in vacuo. The crude product waspurified by chromatography on the Companion (12 g column, 0-100%AcOEt/DCM) to affordtrans-(1r,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl acetate (0.244 g, 60%) as a brown solid; Rt 2.45 min; m/z 580(M+H)+ (ES+).

(4-(1-(trans-(1r,4s)-4-acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-methylisoxazol-5-yl)methylacetate

A mixture of water (0.293 ml, 16.26 mmol) andtrans-(1r,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexylacetate (0.244 g, 0.421 mmol) and (4-bromo-3-methylisoxazol-5-yl)methylacetate (0.068 g, 0.292 mmol) in PdCl2(dppf) (0.021 g, 0.029 mmol) andPOTASSIUM CARBONATE (0.121 g, 0.877 mmol) was purged with N2 for 10 mn.1,4-DIOXANE (1.626 ml, 19.01 mmol) was then added. The reaction mixturewas heated at 90° C. for 4.5 h. The reaction was cooled down to RT andconcentrated in vacuo. The organic layer was concentrated in vacuo thenwas purified by flash chromatography (12 g, DCM/MeOH: 100/0 to 90/10)then by flash chromatography column (12 g, DCM/MeOH: 100/0 to 90/10) toafford(4-(1-(trans-(1r,4r)-4-acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-methylisoxazol-5-yl)methylacetate (100 mg, 39%) was isolated as a brown solid; Rt 2.17 min; m/z607 (M+H)+ (ES+).

(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(4-(1-(trans-(1r,4s)-4-acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-methylisoxazol-5-yl)methylacetate (107 mg, 0.123 mmol) was diluted in MeOH (4.995 mL, 123 mmol).Potassium carbonate (171 mg, 1.235 mmol) was added and the suspensionwas stirred at RT for 24 h. The reaction mixture was concentrated invacuo, then the solid was dissolved in DCM (5 mL), sonicated and dryloaded on silica gel. The compound was purified by flash chromatography(DCM/MeOH: 100/0 to 90/10) to give(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(30 mg, 46%) was isolated as a white solid; Rt 1.55 min; m/z 523 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.88-7.78 (m, 2H), 7.69 (d, J=1.6 Hz, 1H),7.38 (dt, J=10.7, 9.2 Hz, 1H), 7.28 (dd, J=8.5, 1.7 Hz, 1H), 7.20-7.10(m, 1H), 6.11 (dd, J=8.2, 2.0 Hz, 1H), 5.42 (t, J=5.5 Hz, 1H), 4.75 (d,J=4.2 Hz, 1H), 4.56-4.39 (m+d, 3H), 3.78-3.66 (m, 1H), 2.82-2.53 (m,3H), 2.41 (s, 3H), 2.39-2.22 (m, 2H), 2.14-2.04 (m, 1H), 2.04-1.92 (m,2H), 1.88-1.76 (m, 1H), 1.76-1.68 (m, 1H), 1.59-1.36 (m, 2H).

Example 177:(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(4-(1-((1r,4S)-4-Acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-5-methylisoxazol-3-yl)methylacetate

(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(4-(1-((1r,4S)-4-Acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-5-methylisoxazol-3-yl)methylacetate (36.9 mg, 0.054 mmol) was diluted in MeOH (2166 μL, 53.5 mmol).Potassium carbonate (22.19 mg, 0.161 mmol) was added and the suspensionwas stirred at RT for 2h. The reaction mixture was concentrated in vacuoand then the solid was dissolved in DCM (5 mL), sonicated and dry loadedon silica gel. The compound was purified by chromatography column(DCM/MeOH: 100/0 to 90/10) to afford(S)-1-(3,4-Difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(8 mg, 28%) as a white solid; Rt 1.61 min; m/z 523 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.88-7.77 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.38 (q, J=10.6,9.2 Hz, 1H), 7.28 (dd, J=8.5, 1.7 Hz, 1H), 7.20-7.10 (m, 1H), 6.11 (dd,J=8.2, 2.0 Hz, 1H), 5.42 (t, J=5.5 Hz, 1H), 4.75 (d, J=4.2 Hz, 1H),4.54-4.40 (m+d, 3H), 3.77-3.67 (m, 1H), 2.81-2.67 (m, 1H), 2.67-2.53 (m,1H), 2.41 (s, 3H), 2.38-2.26 (m, 2H), 2.11-2.03 (m, 1H), 2.03-1.91 (m,3H), 1.85-1.77 (m, 1H), 1.76-1.68 (m, 1H), 1.59-1.39 (m, 2H).

Example 178:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.163 mmol) in pyridine (3 mL) at 40° C. then stirred for 15minutes. Phenylboronic acid (100 mg, 0.820 mmol) was added then themixture was stirred at 40° C. overnight. The mixture was diluted withdichloromethane (10 mL) then washed with water (2×15 mL) followed bysaturated brine (15 mL). The organic phase was concentrated underreduced pressure then purified by flash chromatography on the Companion(4 g column, 0-50% THF/DCM). The product was triturated in diethyl etherto afford((S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one(64 mg, 74%) as a white solid; Rt 2.12 min; m/z 505 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.73 (dd, J=1.7, 0.6 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H),7.31-7.09 (m, 6H), 5.76-5.64 (m, 1H), 4.62 (t, J=12.4 Hz, 1H), 2.67-2.52(m, 2H), 2.45-2.31 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.23-1.79 (m,9H), 1.10-1.01 (m, 1H).

Example 179:(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(S)—N-(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide

TEA (1.58 mL, 11.35 mmol) was added to a solution ofN¹-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine(1.11 g, 3.78 mmol), (S)-6-oxopiperidine-2-carboxylic acid (0.596 g,4.16 mmol) and HATU (1.583 g, 4.16 mmol) in DMF (10 mL) then stirred atRT for 18 h. The mixture was diluted with water (30 mL) then extractedwith DCM (100 mL). The organic phase was washed with water (30 mL) thenpassed through a PhaseSep cartridge and concentrated in vacuo. Theresidue was purified by flash chromatography to afford(S)—N-(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide(751 mg, 46%) as a viscous red brown oil; Rt 1.78 min; m/z 419 (M+H)+(ES+).

(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one

A solution of(S)—N-(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide(1.58 g, 3.78 mmol) in acetic acid (5 mL) was heated at 80° C. for 18 h.The solvent was removed in vacuo, the crude product taken up in theminimum of DCM, and purified by chromatography (40 g silica, 0-10% MeOHin DCM, gradient elution). Product fractions were combined andconcentrated in vacuo to afford(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(497 mg, 32%) as a beige solid; Rt 1.70 min; m/z 401 (M+H)+ (ES+).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one

To a scintillation vial containing(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(100 mg, 0.250 mmol) in pyridine (3 mL) was added CuTMEDA (58.0 mg,0.125 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-chloro-4-methoxyphenyl)boronic acid (116 mg, 0.624 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 hrs. Thereaction mixture was cooled to RT and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO₄) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-4% MeOH inDCM, gradient elution) to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(74 mg, 55%) as a beige solid; Rt 2.17 min; m/z 541 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.77 (dd, J=1.7, 0.6 Hz, 1H), 7.59 (dd, J=8.5, 0.6 Hz, 1H),7.36 (d, J=2.5 Hz, 1H), 7.28 (dd, J=8.5, 1.7 Hz, 1H), 7.14 (dd, J=8.8,2.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 5.69 (t, J=4.8 Hz, 1H), 5.14 (dq,J=8.8, 3.7 Hz, 1H), 3.76 (s, 3H), 3.57-3.33 (m, 2H), 3.03 (m, 1H),2.60-2.53 (m, 2H), 2.50-2.31 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.08(d, J=5.6 Hz, 1H), 1.87 (s, 1H), 1.77 (s, 1H).

Example 180:(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one

To a scintillation vial containing(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(100 mg, 0.250 mmol) in pyridine (3 ml) was added CuTMEDA (58.0 mg,0.125 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3,4-difluorophenyl)boronic acid (99 mg, 0.624 mmol) added and thereaction mixture was left to stir at 40° C. for 18 h. The reactionmixture was cooled to RT and partitioned between ethyl acetate (20 mL)and water (10 mL). The organic phase was washed with further portion ofwater (2×10 mL), dried (MgSO₄) and concentrated in vacuo. The cruderesidue was purified by flash chromatography (4 g silica, 0-4% MeOH inDCM, gradient elution) to afford(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one(78 mg, 60%) as an off white solid; Rt 2.18 min; m/z 513 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 7.77 (d, J=1.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H),7.43-7.24 (m, 3H), 7.14-7.05 (m, 1H), 5.78-5.69 (m, 1H), 5.14 (td,J=8.5, 3.7 Hz, 1H), 3.58-3.33 (m, 2H), 3.10 (m, 1H), 2.61-2.46 (m, 2H),2.40 (m, 5H), 2.24 (s, 3H), 2.07 (d, J=4.8 Hz, 1H), 1.83 (m, 1H), 1.77(m, 1H).

Example 181:(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

To a scintillation vial containing(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(100 mg, 0.250 mmol) in pyridine (3 mL) was added CuTMEDA (58.0 mg,0.125 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-fluoro-4-methoxyphenyl)boronic acid (106 mg, 0.624 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 h. Thereaction mixture was cooled to RT and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO₄) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-4% MeOH inDCM, gradient elution) to afford(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (85 mg, 64%)as a beige solid; Rt 2.09 min; m/z 525 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ:7.77 (dd, J=1.7, 0.6 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.4,1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.3 Hz, 1H), 7.08-6.95 (m, 2H), 5.68 (t,J=4.7 Hz, 1H), 5.14 (td, J=8.4, 3.7 Hz, 1H), 3.75 (s, 3H), 3.47 (dt,J=16.8, 8.5 Hz, 1H), 3.36-3.26 (m, 2H), 3.09-2.97 (m, 1H), 2.59-2.41 (m,2H), 2.41 (s, 3H), 2.36 (m, 1H), 2.24 (s, 3H), 2.07 (d, J=13.0 Hz, 1H),1.87 (m, 1H), 1.76 (m, 1H).

Example 182: (1S,4r)-methyl4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(1S,4r)-methyl4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

CuTMEDA (0.722 g, 1.554 mmol) was added to a stirred solution of(1S,4r)-methyl4-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(1.4 g, 3.11 mmol) in pyridine (37.4 mL, 463 mmol) then the mixture wasstirred for 15 min at 40° C. (3,4-Difluorophenyl)boronic acid (1.300 g,8.23 mmol) was added then the mixture was heated to 40° C. for 2.5 hthen stirred at RT overnight. The mixture was concentrated in vacuo togive a green residue which was diluted with ethyl acetate (100 mL) andfiltered through a pad of Celite to remove the copper salts. The organicphase was washed with water (3×100 mL) and saturated brine (100 mL),dried (MgSO4), filtered and concentrated under reduced pressure and thecrude product was purified by flash chromatography on the Companion (24g column, DCM/MeOH: 100/0 to 90/10) then repurified by flashchromatography (12 g, DCM/AcOEt: 100/0 to 0/100) to afford(1S,4r)-methyl4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(1.0 g, 55%) was isolated as a pinkish foam; Rt 2.15 min; m/z 563 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 7.85 (d, J=8.4 Hz, 1H), 7.69 (d, J=1.6 Hz,1H), 7.42-7.28 (m, 2H), 7.14 (dd, J=8.4, 1.7 Hz, 1H), 7.09-7.00 (m, 1H),5.78 (t, J=4.6 Hz, 1H), 4.44-4.32 (m, 1H), 3.63 (s, 3H), 2.71-2.59 (m,1H), 2.59-2.43 (m, 2H), 2.40 (s, 3H), 2.39-2.25 (m, 2H), 2.23 (s, 3H),2.22-2.13 (m, 1H), 2.08-1.99 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.72 (m,2H), 1.71-1.56 (m, 2H), 1.28-1.18 (m, 1H).

Example 183:(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid

A solution of LiOH (0.054 g, 2.240 mmol) in water (15.85 mL, 880 mmol)was added to a solution of (1S,4r)-methyl4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate(0.900 g, 1.600 mmol) in THF (15.86 mL, 194 mmol). The solution wasstirred at 50° C. for 2 hours. At RT, aqueous 1M HCl (3 ml) was added(pH=2). The resulting white solid was filtered, washed with water (3×10mL), washed with diethyl ether (3×5 mL). The solid was dried undervacuum at 40° C. for 15 hours to afford(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (698 mg, 77%) as a white solid; Rt 1.86 min; m/z 549(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 12.17 (s, 1H), 7.86 (d, J=8.6 Hz, 1H),7.70 (d, J=1.6 Hz, 1H), 7.43-7.28 (m, 2H), 7.15 (d, J=8.0 Hz, 1H),7.09-7.00 (m, OH), 5.80 (t, 1H), 4.44-4.30 (m, 1H), 2.64-2.45 (m, 2H),2.41 (s, 3H), 2.39-2.25 (m, 2H), 2.24 (s, 3H), 2.21-2.10 (m, 1H),2.08-2.00 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.73 (m, 2H), 1.68-1.53 (m,2H), 1.28-1.18 (m, 1H).

Example 184:(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclohexanecarboxamide(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclohexanecarboxamide

DIPEA (0.040 mL, 0.228 mmol) was added to a solution of propan-1-amine(8.23 μl, 0.100 mmol),(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (50 mg, 0.091 mmol) and HATU (45.0 mg, 0.118 mmol) inDMF (0.303 mL, 3.91 mmol). The brown solution was stirred at RT for 15h, then the reaction mixture was diluted in AcOEt (30 mL) and washedwith water (3×20 mL) and with brine (20 mL). The organic was dried onMgSO₄, filtered and concentrated in vacuo to give a beige foam as crudematerial. The crude was purified by flash chromatography on theCompanion (4 g, DCM/AcOEt: 100/0 to 0/100) to give(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclohexanecarboxamide (36 mg, 66% yield) was isolated as a white solid; Rt 1.99min; m/z 590 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 7.77-7.69 (m, 3H),7.43-7.28 (m, 2H), 7.16 (dd, J=8.5, 1.6 Hz, 1H), 7.09-7.01 (m, 1H), 5.79(t, J=4.9 Hz, 1H), 4.46-4.31 (m, 1H), 3.02 (q, J=6.5 Hz, 2H), 2.63-2.52(m, 2H), 2.43-2.39 (m, 3H), 2.39-2.26 (m, 2H), 2.24 (s, 3H), 2.22-1.94(m, 4H), 1.93-1.74 (m, 4H), 1.74-1.59 (m, 2H), 1.41 (h, J=7.3 Hz, 2H),1.29-1.20 (m, 1H), 0.84 (t, J=7.4 Hz, 3H).

Example 185:(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide

DIPEA (0.040 mL, 0.228 mmol) was added to a solution ofN-methylpropan-1-amine (10.27 μl, 0.100 mmol),(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (50mg, 0.091 mmol) and HATU (45.0 mg, 0.118 mmol) in DMF (0.303 mL, 3.91mmol). The yellow solution was stirred at RT for 2 h. The reactionmixture was diluted in AcOEt (30 mL) and washed with water (3×20 mL) andwith brine (20 mL). The organic was dried on MgSO4, filtered andconcentrated in vacuo to give a beige foam as crude material, which waspurified by flash chromatography on the Companion (4 g, DCM/AcOEt: 100/0to 0/100) to give((1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide(35.1 mg, 62%) as a yellow glass; Rt 2.12 min; m/z 604 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 7.97-7.86 (m, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.44-7.27(m, 2H), 7.15 (ddd, J=8.5, 4.9, 1.7 Hz, 1H), 7.10-7.00 (m, 1H),5.88-5.78 (m, 1H), 4.47-4.31 (m, 1H), 3.37 (t, J=7.3 Hz, 1H), 3.30-3.21(m, 1H), 3.06 (s, 1.6H), 2.96-2.89 (m, 1H), 2.80 (s, 11.4H), 2.60-2.52(m, 1H), 2.44-2.29 (m+d, 6H), 2.29-2.13 (m+d, 4H), 2.09-1.91 (m, 2H),1.86-1.61 (m, 6H), 1.61-1.52 (m, 1H), 1.46 (h, J=7.3 Hz, 1H), 1.22-1.13(m, 1H), 0.91 (t, J=7.3 Hz, 1.4H), 0.81 (t, J=7.4 Hz, 1.6H).

Example 186:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)piperidin-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.163 mmol) in pyridine (3 mL) at 40° C. then stirred for 15minutes. (6-fluoropyridin-3-yl)boronic acid (100 mg, 0.710 mmol) wasadded then the mixture was stirred at 40° C. overnight. The mixture wasdiluted with dichloromethane (10 mL) then washed with water (2×15 mL)followed by saturated brine (15 mL). The organic phase was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% THF/DCM). The product was triturated in diethyl etherto afford (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)piperidin-2-one (11 mg, 12%) as a white solid; Rt 2.10 min; m/z 524 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.16-8.04 (m, 1H), 7.85 (ddd, J=8.7, 7.3, 2.7Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.23 (dd,J=8.4, 1.7 Hz, 1H), 7.14 (dd, J=8.7, 3.0 Hz, 1H), 5.77 (t, J=4.6 Hz,1H), 4.63 (t, J=12.4 Hz, 1H), 2.60 (dt, J=9.2, 5.3 Hz, 2H), 2.50-2.42(m, 1H), 2.41 (s, 3H), 2.40-2.25 (m, 2H), 2.24 (s, 3H), 2.15 (dd,J=34.4, 15.8 Hz, 5H), 1.96 (d, J=12.1 Hz, 2H), 1.87-1.77 (m, 1H),1.44-1.36 (m, 1H).

Example 187:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)piperidin-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(70 mg, 0.163 mmol) in pyridine (3 mL) at 40° C. then stirred for 15minutes. (5-fluoropyridin-3-yl)boronic acid (100 mg, 0.710 mmol) wasadded then the mixture was stirred at 40° C. overnight. The mixture wasdiluted with dichloromethane (10 mL) then washed with water (2×15 mL)followed by saturated brine (15 mL). The organic phase was concentratedunder reduced pressure then purified by chromatography on the Companion(4 g column, 0-50% THF/DCM). The product was triturated in diethyl etherto afford(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)piperidin-2-one (5 mg, 6%) as a white solid; Rt 2.06 min;m/z 524 (M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.38 (d, J=2.6 Hz, 1H), 8.34(t, J=1.7 Hz, 1H), 7.75-7.72 (m, 1H), 7.69 (ddd, J=10.3, 2.7, 1.9 Hz,1H), 7.54 (d, J=8.5 Hz, 1H), 7.23 (dd, J=8.5, 1.7 Hz, 1H), 5.85 (t,J=4.6 Hz, 1H), 4.73-4.55 (m, 1H), 2.66-2.53 (m, 2H), 2.47-2.26 (m, 3H),2.41 (s, 3H), 2.24 (s, 3H), 2.13 (t, J=23.0 Hz, 5H), 1.98 (d, J=12.8 Hz,2H), 1.82 (s, 1H), 1.42 (d, J=12.5 Hz, 1H).

Example 188:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)piperidin-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(100 mg, 0.233 mmol) in pyridine (3 mL) at 40° C. then stirred for 15minutes. pyridin-3-ylboronic acid (100 mg, 0.814 mmol) was added thenthe mixture was stirred at 40° C. overnight. The mixture was dilutedwith dichloromethane (10 mL) then washed with water (2×15 mL) followedby saturated brine (15 mL). The organic phase was concentrated underreduced pressure then purified by chromatography on the Companion (4 gcolumn, 0-50% THF/DCM) then purified by preparative HPLC (Waters, Acidic(0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mmcolumn, 25-70% MeCN in Water) to(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)piperidin-2-one(26 mg, 21%) as a white solid; Rt 1.87 min; m/z 506 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 8.43 (dd, J=2.5, 0.7 Hz, 1H), 8.32 (dd, J=4.7, 1.5 Hz, 1H),7.74 (d, J=1.6 Hz, 1H), 7.65 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 7.52 (d,J=8.5 Hz, 1H), 7.33 (ddd, J=8.1, 4.7, 0.8 Hz, 1H), 7.22 (dd, J=8.5, 1.7Hz, 1H), 5.79 (t, J=4.6 Hz, 1H), 4.72-4.56 (m, 1H), 2.66-2.52 (m, 2H),2.49-2.42 (m, 1H), 2.41 (s, 3H), 2.40-2.25 (m, 2H), 2.24 (s, 3H),2.22-1.90 (m, 7H), 1.83 (s, 1H), 1.33-1.17 (m, 1H).

Example 195:(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyrimidin-5-yl)piperidin-2-one(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyrimidin-5-yl)piperidin-2-one

CuTMEDA (27.1 mg, 0.058 mmol) was added to a stirred solution of(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one(50 mg, 0.117 mmol) in PYRIDINE (2 ml, 24.73 mmol) then the mixture wasstirred for 15 min at 40° C. pyrimidin-5-ylboronic acid (38.3 mg, 0.309mmol) was added then the mixture was heated to 40° C. for 2 h. Themixture was diluted with ethyl acetate (25 mL) then washed with water(3×25 mL) and saturated brine (25 mL). The mixture was concentratedunder reduced pressure then the crude product was purified bychromatography on silica gel (24 g column, 0-10% MeOH/DCM) to afford((S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyrimidin-5-yl)piperidin-2-one(8 mg, 13%) as a colourless solid; Rt 1.96 min; m/z 507 (M+H)+ (ES+); 1HNMR (d6-DMSO) δ: 8.94 (s, 1H), 8.74 (s, 2H), 7.77-7.67 (m, 1H), 7.54 (d,J=8.5 Hz, 1H), 7.23 (dd, J=8.5, 1.7 Hz, 1H), 5.89 (t, J=4.5 Hz, 1H),4.77-4.54 (m, 1H), 2.66-2.58 (m, 2H), 2.48-2.44 (m, 2H), 2.40 (s, 3H),2.37-2.26 (m, 2H), 2.24 (s, 3H), 2.21-2.05 (m, 4H), 2.05-1.80 (m, 3H),1.56-1.43 (m, 1H).

General Route E: Non-Convergent Approach to Azabenzimidazole AnaloguesExample 189(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one

To a scintillation vial containing(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(100 mg, 0.244 mmol) in pyridine (3 ml) was added CuTMEDA (56.7 mg,0.122 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-chloro-4-methoxyphenyl)boronic acid (114 mg, 0.611 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 hrs. Thereaction mixture was cooled to rt and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO4) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-10% MeOH inDCM, gradient elution). Product fractions were combined and concentratedin vacuo. The residue was triturated with ether to afford(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(66 mg, 49%) as a beige solid; Rt 1.76 min; m/z 550 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 8.30 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.39 (d,J=2.4 Hz, 1H), 7.10 (dd, J=8.8, 2.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H),5.79 (t, J=4.8 Hz, 1H), 4.70 (d, J=4.1 Hz, 1H), 4.35 (m, 1H), 3.76 (s,3H), 3.52 (m, 1H), 2.69-2.46 (m, 3H), 2.42 (s, 3H), 2.38 (m, 1H), 2.25(s, 3H), 2.06 (m, 2H), 1.95 (d, J=12.5 Hz, 1H), 1.83 (m, 3H), 1.72 (d,J=12.5 Hz, 1H), 1.39 (m, 2H), 1.16-1.06 (m, 1H).

Example 190:(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one

To a scintillation vial containing(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(100 mg, 0.244 mmol) in pyridine (3 ml) was added CuTMEDA (56.7 mg,0.122 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3,4-difluorophenyl)boronic acid (96 mg, 0.611 mmol) added and thereaction mixture was left to stir at 40° C. for 18 hrs. The reactionmixture was cooled to rt and partitioned between ethyl acetate (20 mL)and water (10 mL). The organic phase was washed with further portion ofwater (2×10 mL), dried (MgSO4) and concentrated in vacuo. The cruderesidue was purified by chromatography (4 g silica, 0-10% MeOH in DCM,gradient elution). Product fractions were combined and concentrated invacuo. The residue was triturated with ether to afford(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(61 mg, 47%) as a cream solid; Rt 1.77 min; m/z 522 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.45-7.29(m, 2H), 7.10-7.01 (m, 1H), 5.82 (t, J=4.5 Hz, 1H), 4.71 (d, J=4.2 Hz,1H), 4.35 (m, 1H), 3.53 (m, 1H), 2.67-2.48 (m, 2H), 2.48-2.36 (m, 4H),2.25 (s, 3H), 2.07 (m, 1H), 1.96 (d, J=12.2 Hz, 2H), 1.87 (d, J=12.0 Hz,1H), 1.76 (t, J=15.8 Hz, 3H), 1.38 (m, 3H), 1.20 (d, J=12.5 Hz, 1H).

Example 191:(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

To a scintillation vial containing(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(100 mg, 0.244 mmol) in pyridine (3 ml) was added CuTMEDA (56.7 mg,0.122 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-fluoro-4-methoxyphenyl)boronic acid (104 mg, 0.611 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 hrs. Thereaction mixture was cooled to rt and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO4) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-10% MeOH inDCM, gradient elution). Product fractions were combined and concentratedin vacuo. The residue was triturated with ether to afford(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (59 mg, 45%) as a beige solid; Rt 1.70 min; m/z 534(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0Hz, 1H), 7.15 (dd, J=12.7, 2.4 Hz, 1H), 7.09-6.93 (m, 2H), 5.77 (t,J=4.6 Hz, 1H), 4.71 (d, J=4.1 Hz, 1H), 4.34 (s, 1H), 3.75 (s, 3H), 3.52(m, 1H), 2.67-2.37 (m, 4H), 2.43 (s, 3H), 2.26 (s, 3H), 2.05 (m, 2H),1.96 (d, J=12.9 Hz, 1H), 1.90-1.78 (m, 2H), 1.74 (d, J=13.2 Hz, 1H),1.38 (t, J=13.6 Hz, 2H), 1.11 (m, 2H).

Example 192:(S)-1-(3-chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

To a scintillation vial containing(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one(100 mg, 0.241 mmol) in pyridine (3 ml) was added CuTMEDA (55.9 mg,0.120 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-chloro-4-methoxyphenyl)boronic acid (112 mg, 0.602 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 hrs. Thereaction mixture was cooled to rt and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO4) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-10% MeOH inDCM, gradient elution). Product fractions were combined and concentratedin vacuo. The residue was triturated with ether to afford(S)-1-(3-chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one(33 mg, 24%) as a brown solid; Rt 2.35 min; m/z 556 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=2.0 Hz, 1H), 8.10(d, J=2.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.28 (dd, J=9.0, 2.6 Hz, 1H),7.08 (d, J=9.1 Hz, 1H), 6.09 (dd, J=8.3, 2.2 Hz, 1H), 4.78 (s, 1H), 3.77(s, 3H), 2.93 (dt, J=23.5, 11.8 Hz, 2H), 2.83-2.50 (m, 3H), 2.39 (s,3H), 2.23-2.08 (m, 8H), 1.95 (d, J=12.7 Hz, 1H), 1.68 (d, J=12.4 Hz,1H).

Example 193:(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

To a scintillation vial containing(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one(100 mg, 0.241 mmol) in pyridine (3 ml) was added CuTMEDA (55.9 mg,0.120 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3,4-difluorophenyl)boronic acid (95 mg, 0.602 mmol) added and thereaction mixture was left to stir at 40° C. for 18 hrs. The reactionmixture was cooled to rt and partitioned between ethyl acetate (20 mL)and water (10 mL). The organic phase was washed with further portion ofwater (2×10 mL), dried (MgSO4) and concentrated in vacuo. The cruderesidue was purified by chromatography (4 g silica, 0-10% MeOH in DCM,gradient elution). Product fractions were combined and concentrated invacuo. The residue was triturated with ether to afford(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one(70 mg, 55%) as a light pink solid; Rt 2.39 min; m/z 528 (M+H)+ (ES+);1H NMR (d6-DMSO) δ: 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=2.0 Hz, 1H),8.09 (d, J=2.0 Hz, 1H), 7.87 (ddd, J=13.2, 7.4, 2.7 Hz, 1H), 7.39 (dt,J=10.6, 9.2 Hz, 1H), 7.19 (dddd, J=9.0, 3.9, 2.6, 1.5 Hz, 1H), 6.16-6.08(m, 1H), 4.76 (s, 1H), 3.04-2.88 (m, 2H), 2.78-2.63 (m, 2H), 2.61-2.50(m, 1H), 2.39 (s, 3H), 2.21 (s, 3H), 2.21-2.03 (m, 5H), 1.98 (d, J=12.9Hz, 1H), 1.89 (d, J=12.4 Hz, 1H).

Example 194:(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

To a scintillation vial containing(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one(100 mg, 0.241 mmol) in pyridine (3 ml) was added CuTMEDA (55.9 mg,0.120 mmol). The reaction mixture was stirred at 40° C. for 15 minutes,then (3-fluoro-4-methoxyphenyl)boronic acid (102 mg, 0.602 mmol) addedand the reaction mixture was left to stir at 40° C. for 18 hrs. Thereaction mixture was cooled to rt and partitioned between ethyl acetate(20 mL) and water (10 mL). The organic phase was washed with furtherportion of water (2×10 mL), dried (MgSO4) and concentrated in vacuo. Thecrude residue was purified by chromatography (4 g silica, 0-10% MeOH inDCM, gradient elution). Product fractions were combined and concentratedin vacuo. The residue was triturated with ether to afford(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one(38 mg, 29%) as a brown solid; Rt 2.28 min; m/z 540 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 8.34 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.69-7.60(m, 1H), 7.13-7.06 (m, 2H), 6.10-6.02 (m, 1H), 4.77 (s, 1H), 3.75 (s,3H), 3.02-2.84 (m, 2H), 2.82-2.51 (m, 3H), 2.39 (s, 3H), 2.22 (s, 3H),2.22-2.08 (m, 5H), 1.96 (d, J=12.7 Hz, 1H), 1.72 (d, J=12.5 Hz, 1H).

Example 196:(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one

CuTMEDA (0.063 g, 0.136 mmol) was added to a stirred solution of(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(0.1 g, 0.272 mmol) in PYRIDINE (3.28 ml, 40.6 mmol) then the mixturewas stirred for 15 min at 40° C. (3,4-difluorophenyl)boronic acid (0.107g, 0.680 mmol) was added then the mixture was heated to 40° C. for 15 h.The reaction was cooled down to RT. The reaction was cooled down to r.t.The mixture was concentrated in vacuo to give a green residue which wasdiluted with DCM (10 mL). then washed with water (3×10 mL) and saturatedbrine (10 mL). The organic phase was filtered through a phase layerseparator and concentrated under reduced pressure. The crude residue waspurified by flash chromatography (4 g silica, 0-10% MeOH in DCM,gradient elution) to give(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(45 mg, 33%) was isolated as a brown pink solid; Rt 2.17 min; m/z 480(M+H)+ (ES+); 1H NMR (d6-DMSO) δ: 8.31 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9Hz, 1H), 7.41-7.28 (m, 2H), 7.13-7.04 (m, 1H), 5.64 (dd, J=5.7, 2.9 Hz,1H), 4.08 (dd, J=14.1, 6.7 Hz, 1H), 3.85 (dd, J=14.1, 8.8 Hz, 1H),2.64-2.51 (m, 2H), 2.46-2.35 (m+s, 4H), 2.25 (s, 3H), 2.12-2.00 (m, 3H),1.80-1.70 (m, 1H), 0.75 (d, J=6.7 Hz, 3H), 0.50 (d, J=6.6 Hz, 3H).

Example 197:(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

CuTMEDA (0.063 g, 0.136 mmol) was added to a stirred solution of(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one(0.1 g, 0.272 mmol) in PYRIDINE (3.28 ml, 40.6 mmol) then the mixturewas stirred for 15 min at 40° C. (3-fluoro-4-methoxyphenyl)boronic acid(0.116 g, 0.680 mmol) was added then the mixture was heated to 40° C.for 15 h. The reaction was cooled down to RT. The reaction was cooleddown to r.t. The mixture was concentrated in vacuo to give a greenresidue which was diluted with DCM (10 mL) then washed with water (3×10mL) and saturated brine (10 mL). The organic phase was filtered througha phase layer separator and concentrated under reduced pressure. Thecrude residue was purified by chromatography (4 g silica, 0-10% MeOH inDCM, gradient elution) to give(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one(48 mg, 35%) was isolated as a brown glass; Rt 2.02 min; m/z 492 (M+H)+(ES+); 1H NMR (d6-DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.0 Hz,1H), 7.09 (dd, J=12.6, 2.3 Hz, 1H), 7.05-6.95 (m, 2H), 5.58 (dd, J=5.6,2.8 Hz, 1H), 4.05 (dd, J=14.1, 6.7 Hz, 1H), 3.85 (dd, J=14.1, 8.7 Hz,1H), 3.73 (s, 3H), 2.56-2.51 (m, 2H), 2.46-2.34 (m, 4H), 2.26 (s, 3H),2.10-2.00 (m, 3H), 1.79-1.70 (m, 1H), 0.73 (d, J=6.7 Hz, 3H), 0.50 (d,J=6.6 Hz, 3H).

General Route F: Convergent Approach to N-Alkyllactam Analogues Example198:(S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(50 mg, 0.121 mmol) in N,N-dimethylformamide (1 mL) were treated with1.0 M NaHMDS in tetrahydrofuran (125 μl, 0.125 mmol) then stirred atroom temperature for 5 minutes. A solution of benzyl bromide (21 mg,0.123 mmol) in N,N-dimethylformamide (1 mL) were added then the mixtureswere stirred at room temperature for 18 h. The mixture was diluted withwater (6 mL) then extracted with dichloromethane (2×6 mL). The combinedorganic phases were washed with saturated brine (6 mL) then concentratedunder reduced pressure. The crude products were purified bychromatography on the Companion (4 g column, 0-50% THF/DCM) thentriturated in diethyl ether:isohexane (1:1, 8 mL) to afford(S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(42 mg, 66%) as a white solid; Rt 1.97 min; m/z 499 (M+H)+ (ES+); 1H NMR(d6-DMSO) δ: 7.84 (d, J=8.5 Hz, 1H), 7.69 (dd, J=1.7, 0.6 Hz, 1H),7.38-7.24 (m, 3H), 7.21-7.13 (m, 3H), 5.10 (dd, J=7.9, 3.0 Hz, 1H), 4.99(d, J=15.5 Hz, 1H), 4.26 (t, J=12.3 Hz, 1H), 3.79 (d, J=15.5 Hz, 1H),3.37-3.30 (m, 1H), 3.26 (s, 3H), 2.60-2.53 (m, 1H), 2.50-2.42 (m, 2H),2.42 (s, 3H), 2.31-2.12 (m, 2H), 2.25 (s, 3H), 2.10-2.01 (m, 2H),2.01-1.91 (m, 1H), 1.84-1.75 (m, 1H), 1.74-1.64 (m, 1H), 1.39-1.13 (m,2H).

Example 199: Biological Testing Surface Plasmon Resonance (BIAcore)Analysis of Binding to EP300, CBP and BRD4 BD1

BIAcore data for compound binding to EP300 and BRD4 was acquired using aT200 BIAcore instrument at 4° C. His-tagged EP300 Bromodomain(1046-1163), His-tagged CBP Bromodomain (1081-1197) and BRD4 Bromodomain1 (49-170) proteins were captured onto an NTA chip via a combinedcapture and amine coupling method. NTA groups were first chelated with30 mM nickel chloride and then activated with 0.2 MN-ethyl-N′-(diethylaminopropyl)-carbodiimide (EDC) and 0.05 μMN-hydroxysuccimide (NHS).

Bromodomain proteins diluted to 9.6M in PBS 0.05% Tween-20 were injectedat 101/min and covalently bound. Ethanolamine injections were performedto cap unreacted moieties on the surface and remove uncoupled protein. Atypical immobilisation resulted in ˜2-4 kRU of protein immobilised onthe surface.

Test compounds were serially diluted to generate 1, 10, 100, 1000 and10000 nM solutions in running buffer (PBS with 0.005% Tween-20, 0.1%DMSO). Using a flow rate of 90 μL/min throughout, runs consisted ofinjections of compound with escalating concentration, interspersed withbuffer blank runs consisting of 5 repeat injections of running buffer.

Sensorgrams were analyzed with BIAevaluation (GE Healthcare) using a 1:1interaction model to generate k_(a) and k_(d) values to describe thekinetics of binding. K_(D) values were derived from the quotient ofk_(d) and k_(a). Compounds were tested twice against EP300, CBP and/orBRD4 bromodomain surfaces to obtain geometric means of the kinetic andaffinity parameters. All compounds tested gave K_(D) values in the rangeof 0.5-10,000 nM. For instance, against EP300 and CBP, compounds 70-140gave K_(D) values in the range of 1-200 nM.

Cell Viability Assay

The 22Rv1 cell line was obtained from ATCC (UK) and cultured accordingto the supplier's recommendations. Cell growth inhibitory activity ofrepresentative compounds was determined using the CellTiter-Glo®Luminescent Cell Viability Assay kit (Promega, USA).

22Rv1 cells were maintained in RPMI 1640 media containing 10% FoetalBovine Serum, 2 mM Glutamine, 1 mM sodium pyruvate and 100 units ofPenicillin-100 μg of Streptomycin. Cells were incubated at 37° C. in ahumidified atmosphere with 95% 02 and 5% CO₂. 2000 cells were seeded perwell in Poly-D-Lysine (PDL) coated 96-well black clear bottom plates(VWR, UK) in 50u L of growth medium. After 48 hours, medium was removedand replaced with growth medium containing diluted test compounds.Compound dilutions were performed by serially diluting in half logintervals DMSO stocks at a maximum concentration of 10 mM, for a totalof 7 dilutions. A 1 μl aliquot of each dilution point was added to 99 μlof growth medium and 50 μL added to each well containing cells,providing 100 μM compound at the maximum concentration point (1% DMSO).1% DMSO treated cells served as a high control.

Cells were incubated for a further 72 hours at 37° C. and cell viabilitydetermined using the CellTiter-Glo® Luminescent Cell Viability Assayaccording to the manufacturer's instructions. Briefly, a volume ofCellTiter-Glo® reagent equal to the volume of growth media was added toeach well. Plates were shaken for approximately 2 minutes and incubatedat room temperature (22° C.) for 10 minutes. The luminescence signal wasmeasured using an Envision plate reader with an integration time of 1second per well.

All data was normalised to the mean of 6 high-controls. The half maximuminhibitor concentration (IC50) was calculated from a 4-parameterlogistic curve fit of the data using the Dotmatics software (UK). Allcompounds tested gave IC50 values in the range of 100 nM-100 μM,typically from 100 nM-30 μM.

Cell based assays are likely to show some variability due to thecomplexity of the system and it is understood that the results of theseassays may vary as assay conditions are varied. Some level of cellgrowth inhibition is indicative of the compound having some inhibitoryactivity in specified cells, whereas lack of the inhibition below thehighest concentration tested does not necessarily indicate the compoundhas no inhibitory activity on the cells.

Example 200: Tablet Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention are manufactured as follows:

Composition for 10,000 Tablets

Compound of the invention (250 g)

Lactose (800 g)

Corn starch (415 g)Talc powder (30 g)Magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch aremixed. The mixture is then forced through a sieve 0.5 mm mesh size. Cornstarch (10 g) is suspended in warm water (90 ml). The resulting paste isused to granulate the powder. The granulate is dried and broken up intosmall fragments on a sieve of 1.4 mm mesh size. The remaining quantityof starch, talc and magnesium is added, carefully mixed and processedinto tablets.

Example 201: Injectable Formulation

Compound of the invention 200 mg Hydrochloric Acid Solution 0.1M orSodium Hydroxide Solution 0.1M q.s. to pH 4.0 to 7.0 Sterile water q.s.to  10 mL

The compound of the invention is dissolved in most of the water (35°−40°C.) and the pH adjusted to between 4.0 and 7.0 with the hydrochloricacid or the sodium hydroxide as appropriate. The batch is then made upto volume with water and filtered through a sterile micropore filterinto a sterile 10 mL amber glass vial (type 1) and sealed with sterileclosures and overseals.

Example 202: Intramuscular Injection

Compound of the invention 200 mg Benzyl Alcohol 0.10 g Glycofurol 751.45 g Water for injection q.s to 3.00 mL

The compound of the invention is dissolved in the glycofurol. The benzylalcohol is then added and dissolved, and water added to 3 ml. Themixture is then filtered through a sterile micropore filter and sealedin sterile 3 ml glass vials (type 1).

Example 203: Syrup Formulation

Compound of invention 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 gSodium benzoate 0.005 g Flavour 0.0125 mL Purified Water q.s. to 5.00 mL

The compound of the invention is dissolved in a mixture of the glyceroland most of the purified water. An aqueous solution of the sodiumbenzoate is then added to the solution, followed by addition of thesorbitol solution and finally the flavour. The volume is made up withpurified water and mixed well.

1.-17. (canceled)
 18. A method of treating cancer, which methodcomprises administering to a patient in need thereof a compound which isan arylimidazolyl isoxazole of formula (I):

wherein: R⁰ and R, which are the same or different, are each H or C₁-C₆alkyl which is unsubstituted or substituted by OH, —OC(O)R′ or OR′wherein R′ is unsubstituted C₁-C₆ alkyl; W is N or CH; R¹ is a groupwhich is unsubstituted or substituted and is selected from C-linked 4-to 6-membered heterocyclyl; C₃-C₆ cycloalkyl; C₁-C₆ alkyl which isunsubstituted or substituted by C₆-C₁₀ aryl, 5- to 12-memberedN-containing heteroaryl, C₃-C₆ cycloalkyl, OH, —OC(O)R′ or OR′ whereinR′ is as defined above; and a spiro group of the following formula:

Y is —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—; n is 0 or 1; R² is a group selectedfrom C₆-C₁₀ aryl, 5- to 12-membered N-containing heteroaryl, C₃-C₆cycloalkyl and C₅-C₆ cycloalkenyl, wherein the group is unsubstituted orsubstituted and wherein C₆-C₁₀ aryl is optionally fused to a 5- or6-membered heterocyclic ring; or a pharmaceutically acceptable saltthereof.
 19. A method according to claim 18, wherein the arylimidazolylisoxazole has the following formula (Ia):

wherein R¹ is as defined in claim 18; Y′ is —CH₂— or —CH₂CH₂—; andR^(2′) is a group selected from C₆-C₁₀ aryl optionally fused to a 5- or6-membered heterocyclic ring and C₅-C₆ heteroaryl, the group beingunsubstituted or mono-, di- or tri-substituted.
 20. A method accordingto claim 18 wherein, in formula (I), R¹ is selected from the followingstructures:


21. A method according to claim 18, wherein the compound is the Senantiomer (based on the chiral C atom of the pyrrolidin-2-one orpiperidin-2-one ring).
 22. A method according to claim 18, wherein thecompound is selected from the group consisting of:5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one;5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one;5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one;(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-propoxyphenyl)pyrrolidin-2-one;(S)-1-(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2-one;(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one;(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1i-benzo[d]imidazol-2-yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(o-tolyl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one;3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile;(S)-1-(cyclohex-1-en-1-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4,5-difluoro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one;(R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one;(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;Tert-butyl(S)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate;Tert-butyl(R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-beno[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,4s)-4-ethoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(1R,3R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate;(1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclopentylacetate;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-fluoro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(1S,3r)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclobutylacetate;(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(1-(4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propylacetate;(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclobutanecarboxamide;(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(diastereoisomer 1);(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(diastereoisomer 2);(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-di-fluorophenyl)piperidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpiperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one;(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one;(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(1S,4r)-methyl4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate;(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid;(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-propylcyclohexanecarboxamide;(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6-fluoropyridin-3-yl)piperidin-2-one;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5-fluoropyridin-3-yl)piperidin-2-one;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-(1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one;(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-(1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;(S)-1-(3-chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one;(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one;(S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one;(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyrimidin-5-yl)piperidin-2-one;(S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one;(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one;and(S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;and the pharmaceutically acceptable salts thereof.
 23. A methodaccording to claim 18, wherein the cancer is selected from the groupconsisting of a cancer that expresses AR, a cancer that expresses c-Myc,a tumour that harbours loss of function mutations in CBP or p300 and acancer in which there is activation of CBP and/or p300 function.
 24. Amethod according to claim 18 wherein the cancer is selected from thegroup consisting of prostate cancer, breast cancer, bladder cancer, lungcancer and haematological malignancies.
 25. A method according to claim24 wherein the haematological malignancies are selected from the groupconsisting of lymphoma and leukaemia.
 26. A method according to claim 18wherein said compound is administered concurrently or sequentially withradiotherapy; or is administered concurrently, sequentially or as acombined preparation with one or more other therapeutic agent or agents.27. A method according to claim 26 in which the or each othertherapeutic agent is selected from the group consisting of androgenreceptor antagonists; inhibitors of CYP17A1 (17α-hydroxylase/C17,20lyase); cytotoxic chemotherapeutic agents; immune checkpoint inhibitors;inhibitors of PARP (poly ADP ribose polymerase); and inhibitors ofCDK4/6 (cyclin-dependant kinase 4 and 6).
 28. A compound of formula(II):

wherein: R⁰ and R, which are the same or different, are each H or C₁-C₆alkyl which is unsubstituted or substituted by OH, —OC(O)R′ or OR′wherein R′ is unsubstituted C₁-C₆ alkyl; W is N or CH; R¹ is a groupwhich is unsubstituted or substituted and is selected from C-linked 4-to 6-membered heterocyclyl; C₃-C₆ cycloalkyl; C₁-C₆ alkyl which isunsubstituted or substituted by C₆-C₁₀ aryl, 5- to 12-memberedN-containing heteroaryl, C₃-C₆ cycloalkyl, OH, —OC(O)R′ or OR′ whereinR′ is as defined above; and a spiro group of the following formula:

and Y is —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—.
 29. A compound of formula(III):

wherein: R⁰ and R, which are the same or different, are each H or C₁-C₆alkyl which is unsubstituted or substituted by OH, —OC(O)R′ or OR′wherein R′ is unsubstituted C₁-C₆ alkyl; W is N or CH; R¹ is a groupwhich is unsubstituted or substituted and is selected from C-linked 4-to 6-membered heterocyclyl; C₃-C₆ cycloalkyl; C₁-C₆ alkyl which isunsubstituted or substituted by C₆-C₁₀ aryl, 5- to 12-memberedN-containing heteroaryl, C₃-C₆ cycloalkyl, OH, —OC(O)R′ or OR′ whereinR′ is as defined above; and a spiro group of the following formula:

Y is —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—; and R² is a group selected fromC₆-C₁₀ aryl, 5- to 12-membered N-containing heteroaryl, C₃-C₆ cycloalkyland C₅-C₆ cycloalkenyl, wherein the group is unsubstituted orsubstituted and wherein C₆-C₁₀ aryl is optionally fused to a 5- or6-membered heterocyclic ring.
 30. A composition comprising (i) acompound which is an arylimidazolyl isoxazole of formula (I):

wherein: R⁰ and R, which are the same or different, are each H or C₁-C₆alkyl which is unsubstituted or substituted by OH, —OC(O)R′ or OR′wherein R′ is unsubstituted C₁-C₆ alkyl; W is N or CH; R¹ is a groupwhich is unsubstituted or substituted and is selected from C-linked 4-to 6-membered heterocyclyl; C₃-C₆ cycloalkyl; C₁-C₆ alkyl which isunsubstituted or substituted by C₆-C₁₀ aryl, 5- to 12-memberedN-containing heteroaryl, C₃-C₆ cycloalkyl, OH, —OC(O)R′ or OR′ whereinR′ is as defined above; and a spiro group of the following formula:

Y is —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—; n is 0 or 1; R² is a group selectedfrom C₆-C₁₀ aryl, 5- to 12-membered N-containing heteroaryl, C₃-C₆cycloalkyl and C₅-C₆ cycloalkenyl, wherein the group is unsubstituted orsubstituted and wherein C₆-C₁₀ aryl is optionally fused to a 5- or6-membered heterocyclic ring; or a pharmaceutically acceptable saltthereof; and (ii) one or more other therapeutic agent or agents.
 31. Acomposition according to claim 30 wherein the one or more othertherapeutic agent or agents is selected from the group consisting ofandrogen receptor antagonists; inhibitors of CYP17A1(17α-hydroxylase/C17,20 lyase); cytotoxic chemotherapeutic agents;immune checkpoint inhibitors; inhibitors of PARP (poly ADP ribosepolymerase); and inhibitors of CDK4/6 (cyclin-dependant kinase 4 and 6).